U.S. patent application number 09/985366 was filed with the patent office on 2002-09-05 for acylaminoalkyl-substituted benzenesulfonamide derivatives, their preparation, their use and pharmaceutical preparations comprising them.
Invention is credited to Englert, Heinrich Christian, Heitsch, Holger.
Application Number | 20020123494 09/985366 |
Document ID | / |
Family ID | 7662009 |
Filed Date | 2002-09-05 |
United States Patent
Application |
20020123494 |
Kind Code |
A1 |
Heitsch, Holger ; et
al. |
September 5, 2002 |
Acylaminoalkyl-substituted benzenesulfonamide derivatives, their
preparation, their use and pharmaceutical preparations comprising
them
Abstract
One embodiment of the present invention relates to
acylaminoalkyl-substitu- ted benzenesulfonamide derivatives of the
formula (I), 1 in which A, R(1), R(2), X, Y, and Z have the
meanings indicated in the specification, and to pharmaceutically
tolerable salts thereof. The compounds of the invention are
valuable pharmaceutically active compounds that have, for example,
an inhibitory action on ATP-sensitive potassium channels in the
cardiac muscle and/or in the vagal cardiac nerve and are suitable,
for example, for the treatment of disorders of the cardiovascular
system such as coronary heart disease, arrhythmias, cardiac
insufficiency, cardiomyopathies, decreased contractility of the
heart or vagal dysfunction of the heart, or for the prevention of
sudden cardiac death. The invention furthermore relates to
processes for the preparation of the compounds of the formula (I)
and pharmaceutically tolerable salts thereof, their use, and
pharmaceutical preparations comprising them.
Inventors: |
Heitsch, Holger;
(Mainz-Kastel, DE) ; Englert, Heinrich Christian;
(Hofheim, DE) |
Correspondence
Address: |
Finnegan, Henderson,Farabow,
Garrett & Dunner, L.L.P.
1300 I Street, N.W.
Washington
DC
20005-3315
US
|
Family ID: |
7662009 |
Appl. No.: |
09/985366 |
Filed: |
November 2, 2001 |
Current U.S.
Class: |
514/231.2 ;
514/317; 514/459; 514/471; 514/478; 514/592; 544/159; 546/229;
549/356; 549/429; 560/13; 564/40 |
Current CPC
Class: |
C07D 407/12 20130101;
A61P 25/02 20180101; A61P 9/04 20180101; A61P 9/10 20180101; A61P
9/06 20180101; C07C 335/42 20130101; C07D 215/54 20130101; A61P
43/00 20180101; C07C 311/58 20130101; A61P 9/00 20180101 |
Class at
Publication: |
514/231.2 ;
514/317; 514/459; 514/471; 514/592; 514/478; 544/159; 546/229;
549/356; 549/429; 560/13; 564/40 |
International
Class: |
A61K 031/53; A61K
031/445 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 3, 2000 |
DE |
10054481.9 |
Claims
We claim:
1. A compound of the formula (I), 50wherein R(1) is a)
(C.sub.1-C.sub.4)-alkyl; or b) --O--(C.sub.1-C.sub.4)-alkyl, which
is unsubstituted or is substituted by 1, 2, or 3 fluorine atoms; or
c) --O--(C.sub.1-C.sub.4)-alkyl which is substituted by a
substituent chosen from nitro,
((C.sub.1-C.sub.4)-alkyl)carbonylamino,
(C.sub.1-C.sub.4)-alkylamino, di((C.sub.1-C.sub.4)-alkyl)amino,
hydroxycarbonyl, ((C.sub.1-C.sub.4)-alkoxy)carbonyl,
piperidin-1-yl, morpholin4-yl, tetrahydrofuranyl,
tetrahydropyranyl, phenyl and phenoxy; wherein the phenyl group and
the phenoxy group are unsubstituted or are substituted by one or
two identical or different substituents chosen from halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, and
trifluoromethyl; or d)
--O--(C.sub.1-C.sub.4)-alkyl-E(1)-(C.sub.1-C.sub.4- )-alkyl-D(1),
in which D(1) is hydrogen or --E(2)-(C.sub.1-C.sub.4)-alkyl-- D(2),
in which D(2) is hydrogen or --E(3)-(C.sub.1-C.sub.4)-alkyl,
wherein E(1), E(2) and E(3), which are independent of one another
and can be identical or different, are chosen from O, S, and NH; or
e) --O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl, which
is substituted in the terminal alkoxy group by 1, 2, or 3 fluorine
atoms; or f) --O--(C.sub.2-C.sub.4)-alkenyl; or g) --O-phenyl,
which is unsubstituted or is substituted by one or two identical or
different substituents chosen from halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, and
trifluoromethyl; or h) halogen; or i) phenyl, which is
unsubstituted or is substituted by one or two identical or
different substituents chosen from halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy,
--S(O).sub.m--(C.sub.1-C.sub.4)-alkyl, phenyl, amino, hydroxyl,
nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl,
((C.sub.1-C.sub.4)-alkoxy)carbonyl, and formyl; or j)
(C.sub.2-C.sub.5)-alkenyl, which is unsubstituted or is substituted
by a substituent chosen from phenyl, cyano, hydroxycarbonyl, and
((C.sub.1-C.sub.4)-alkoxy)carbonyl; or k)
(C.sub.2-C.sub.5)-alkynyl, which is unsubstituted or is substituted
by a substituent chosen from phenyl and (C.sub.1-C.sub.4)-alkoxy;
or l) 5-membered or 6-membered monocyclic heteroaryl having one or
two identical or different ring heteroatoms chosen from oxygen,
sulfur, and nitrogen; or m) --S(O).sub.m-phenyl, which is
unsubstituted or is substituted by one or two identical or
different substituents chosen from halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy and
trifluoromethyl; R(2) is hydrogen, (C.sub.1-C.sub.6)-alkyl, or
(C.sub.3-C.sub.7)-cycloalky- l, but is not hydrogen if Z is oxygen;
the residues R(3), which are all independent of one another and can
be identical or different, are hydrogen or (C.sub.1-C.sub.3)-alkyl;
A is chosen from: 51 wherein the free bond via which the residue A
is bonded to the amino group in the formula (I) is represented by
the symbol ; X is oxygen or sulfur; Y is --(CR(3).sub.2).sub.n--; Z
is NH or oxygen; m is 0, 1 or 2; n is 1, 2, 3 or 4; or a
stereoisomeric form of a compound of formula (I), or a mixture of
at least two stereoisomeric forms of a compound of formula (I), or
a physiologically tolerable salt of a compound of formula (I).
2. A compound as claimed in claim 1, wherein Z is NH.
3. A compound as claimed in claim 1, wherein R(1) is a) methyl,
ethyl, or isopropyl; or b) methoxy, ethoxy, propoxy,
trifluoromethoxy, 2-fluoroethoxy, or 2,2,2-trifluoroethoxi; or c)
tetrahydrofuran-2-ylmetho- xy, tetrahydropyran-2-ylmethoxy,
2-(morpholin-4-yl)ethoxy, 2-phenoxyethoxy, benzyloxy, or
2-phenylethoxy; or d) 2-methoxyethoxy or 2-ethoxyethoxy; or e)
2-(trifluoromethoxy)ethoxy or 2-(2,2,2-trifluoroethoxy)ethoxy; or
f) allyloxy; or g) phenoxy, 4-fluorophenoxy, 4-methylphenoxy,
4-methoxyphenoxy or 4-trifluoromethylphenoxy; or h) bromine or
iodine; or i) phenyl, 4-methylphenyl, 4-methoxyphenyl,
4-fluorophenyl or 4-trifluoromethylphenyl; or j) allyl; or k)
ethynyl; or l) furyl, thienyl, or pyridyl; or m) --S-phenyl.
4. A compound as claimed in claim 1, wherein R(1) is methoxy,
ethoxy, trifluoromethoxy, 2-methoxyethoxy, 2-ethoxyethoxy,
2-(trifluoromethoxy)ethoxy, 2-(2,2,2-trifluoroethoxy)ethoxy,
tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy, or
benzyloxy.
5. A compound as claimed in claim 1, wherein R(2) is
(C.sub.1-C.sub.4)-alkyl.
6. A compound as claimed in claim 1, wherein R(2) is methyl.
7. A process for the preparation of a compound as claimed in claim
1, comprising a) converting a benzenesulfonamide of the
formula(III), 52 into a benzenesulfonyl iso(thio)cyanate of the
formula (VIII) 53b) reacting the compound of the formula (VIII)
with an amine of the formula R(2)--NH.sub.2 or an alcohol of the
formula R(2)--OH to give a compund of the formula (I), and c)
optionally reacting a compound of the formula (I) with a suitable
reagent to form a physiologically tolerable salt.
8. A process for the preparation of a compound as claimed in claim
1 in which Z is NH, comprising a) reacting a benzenesulfonamide of
the formula (III), 54 or a salt thereof with an iso(thio)cyanate of
the formula R(2)--N.dbd.C.dbd.X, to give a compound of the formula
(I), and b) optionally reacting a compound of the formula (I) with
a suitable reagent to form a physiologically tolerable salt.
9. A process for the preparation of a compound as claimed in claim
1 in which Z is NH and X is oxygen, comprising a) reacting a
benzenesulfonamide of the formula (III) 55 or a salt thereof with a
trichloroacetamide of the formula Cl.sub.3C--CO--NH--R(2), to give
a compound of the formula (I), and b) optionally reacting a
compound of the formula (I) with a suitable reagent to form a
physiologically tolerable salt.
10. A process for the preparation of a compound as claimed in claim
1 in which Z is NH and X is oxygen, comprising a) desulfurizing the
corresponding compound of the formula (I) in which Z is NH and X is
sulfur on the thiourea group to give a compound of the formula (I),
and b) optionally reacting a compound of the formula (I) with a
suitable reagent to form a physiologically tolerable salt.
11. A composition, comprising at least one compound as claimed in
claim 1 and a carrier.
12. A pharmaceutical composition, comprising an effective amount of
at least one compound as claimed in claim 1 and a pharmaceutically
tolerable carrier.
13. A pharmaceutical composition for inhibiting ATP-sensitive
potassium channels, comprising an effective amount of at least one
compound as claimed in claim 1 and a pharmaceutically tolerable
carrier.
14. A pharmaceutical composition for stimulating the vagal nervous
system, comprising an effective amount of at least one compound as
claimed in claim 1 and a pharmaceutically tolerable carrier.
15. A pharmaceutical composition for treating a dysfunction of the
autonomic nervous system of the heart, comprising an effective
amount of at least one compound as claimed in claim 1 and a
pharmaceutically tolerable carrier.
16. A pharmaceutical composition for treating a person susceptible
to sudden cardiac death, comprising an effective amount of at least
one compound as claimed in claim 1 and a pharmaceutically tolerable
carrier.
17. A pharmaceutical composition for treating vagal dysfunction in
the heart, comprising an effective amount of at least one compound
as claimed in claim 1 and a pharmaceutically tolerable carrier.
18. A method of inhibiting ATP-sensitive potassium channels,
comprising administering to a patient in need thereof an effective
amount of at least one compound as claimed in claim 1.
19. A method of stimulating the vagal nervous system, comprising
administering to a patient in need thereof an effective amount of
at least one compound as claimed in claim 1.
20. A method of treating a dysfunction of the autonomic nervous
system of the heart, comprising administering to a patient in need
thereof an effective amount of at least one compound as claimed in
claim 1.
21. A method of treating a disease, comprising administering to a
patient in need thereof an effective amount of at least one
compound as claimed in claim 1, wherein the disease is chosen from
cardiovascular diseases, ischemic conditions of the heart, coronary
heart disease, weakened myocardial contractile force, angina
pectoris, cardiac insufficiency, cardiomyopathies, cardiac
hypertrophy, and cardiac arrhythmias.
22. A method of treating a person susceptible to sudden cardiac
death, comprising administering to a patient in need thereof an
effective amount of at least one compound as claimed in claim
1.
23. A method according to claim 22, wherein the patient is a post
infarct patient.
24. A method of improving cardiac function, comprising
administering to a patient in need thereof an effective amount of
at least one compound as claimed in claim 1.
25. A method of treating vagal dysfunction in the heart, comprising
administering to a patient in need thereof an effective amount of
at least one compound as claimed in claim 1.
Description
[0001] This application claims the benefit of the filing date of
German Patent Application Number 10054481.9, filed on Nov. 3, 2000,
which application is hereby incorporated by reference.
[0002] One embodiment of the present invention relates to
acylaminoalkyl-substituted benzenesulfonamide derivatives of the
formula (I), 2
[0003] in which A, R(1), R(2), X, Y and Z have the meanings
indicated below. The compounds of the formula (I) are valuable
pharmaceutically active compounds that have, for example, an
inhibitory action on ATP-sensitive potassium channels in the
cardiac muscle and/or in the vagal cardiac nerve and are suitable,
for example, for the treatment of disorders of the cardiovascular
system such as coronary heart disease, arrhythmias, cardiac
insufficiency, cardiomyopathies, decreased contractility of the
heart or vagal dysfunction of the heart, or for the prevention of
sudden cardiac death. Another embodiment of the invention relates
to processes for the preparation of compounds of the formula (I),
their use and pharmaceutical preparations comprising them.
[0004] For certain benzenesulfonylureas, a blood-sugar-lowering
action has been described. A prototype of such blood-sugar-lowering
sulfonylureas is glibenclamide, which is used therapeutically as an
agent for the treatment of diabetes mellitus. Glibenclamide blocks
ATP-sensitive potassium channels and is used in research as a tool
for the exploration of potassium channels of this type. In addition
to its blood-sugar-lowering action, glibenclamide has other actions
that are attributed to the blockade of precisely these
ATP-sensitive potassium channels but that hitherto can still not be
used therapeutically. These include, for example, an
antifibrillatory action on the heart. In the treatment of
ventricular fibrillation or its early stages with glibenclamide
however, the marked blood-sugar-lowering simultaneously produced by
this substance would be undesirable or even dangerous, as it can
further worsen the condition of the patient, so that glibenclamide
is not suitable clinically as an antiarrhythmic.
[0005] Various patent documents, for example U.S. Pat. No.
5,574,069, U.S. Pat. No. 5,698,596, U.S. Pat. No. 5,476,850, U.S.
Pat. No. 5,652,268 or WO-A-00/03978, disclose antifibrillatory
benzenesulfonylureas and -thioureas having reduced
blood-sugar-lowering action. WO-A-00/15204 describes the action of
some of these compounds on the autonomic nervous system. The
properties of these compounds, however, are still not satisfactory
in various respects, and there is an ongoing need for compounds
having a more favorable pharmacodynamic and pharmacokinetic
property profile that are better suited, for example, for the
treatment of a disturbed cardiac rhythm and its consequences such
as sudden cardiac death or a weakened myocardial contractile
force.
[0006] Various benzenesulfonylureas having an acylaminoalkyl
substituent, in which the acyl group can also be derived, inter
alia, from cinnamic acids, and the blood-sugar-lowering action of
these compounds are disclosed in DE-A-1443878, U.S. Pat. No.
3,454,636, DE-A-1518877 and U.S. Pat. No. 4,066,639. The
benzenesulfonylureas that are described in GB-A-1116355 are just so
characterized by a blood-sugar-lowering action, among them some
specific benzenesulfonylureas that contain a
heteroarylacryloyl-aminoalkyl group in the para position to the
sulfonylurea group. In WO-A-00/71513 (international patent
application PCT/EP00/04091) certain cinnamoylaminoalkyl-substituted
benzenesulfonamide derivatives are described, which are
distinguished by a marked action on ATP-sensitive potassium
channels in the heart. Further investigations showed that the
benzenesulfonamide derivatives of the present invention, which
contain acylaminoalkyl substituent in the meta position to the
sulfonyl group, show a marked action on ATP-sensitive potassium
channels of the cardiac muscle and/or of the vagal cardiac nerve,
without having a marked action on pancreatic potassium channels and
thus are valuable pharmaceutical active compounds, for example, for
the treatment of disorders of the cardiovascular system.
[0007] Another embodiment of the present invention relates to
compounds of the formula(I), 3
[0008] in which
[0009] R(1) is
[0010] 1) (C.sub.1-C.sub.4)-alkyl; or
[0011] 2) --O--(C.sub.1-C.sub.4)-alkyl which is unsubstituted or is
substituted by 1, 2 or 3 fluorine atoms; or
[0012] 3) --O--(C.sub.1-C.sub.4)-alkyl which is substituted by a
substituent chosen from nitro,
((C.sub.1-C.sub.4)-alkyl)carbonylamino,
(C.sub.1-C.sub.4)-alkylamino, di((C.sub.1-C.sub.4)-alkyl)amino,
hydroxycarbonyl, ((C.sub.1-C.sub.4)-alkoxy)carbonyl,
piperidin-1-yl, morpholin-4-yl, tetrahydrofuranyl,
tetrahydropyranyl, phenyl, and phenoxy; where the phenyl group and
the phenoxy group are unsubstituted or are substituted by one or
two identical or different substituents chosen from halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, and
trifluoromethyl; or
[0013] 4)
--O--(C.sub.1-C.sub.4)-alkyl-E(1)-(C.sub.1-C.sub.4)-alkyl-D(1), in
which D(1) is hydrogen or --E(2)-(C.sub.1-C.sub.4)-alkyl-D(2), in
which D(2) is hydrogen or --E(3)-(C.sub.1-C.sub.4)-alkyl, where
E(1), E(2) and E(3), which are independent of one another and can
be identical or different, are O, S, or NH; or
[0014] 5) --O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl,
which is substituted in the terminal alkoxy group by 1, 2 or 3
fluorine atoms; or
[0015] 6) --O--(C.sub.2-C.sub.4)-alkenyl; or
[0016] 7) --O-phenyl which is unsubstituted or is substituted by
one or two identical or different substituents chosen from halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, and
trifluoromethyl; or
[0017] 8) halogen; or
[0018] 9) phenyl, which is unsubstituted or is substituted by one
or two identical or different substituents chosen from halogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy,
--S(O).sub.m--(C.sub.1-C.sub.4)-alkyl, phenyl, amino, hydroxyl,
nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl,
((C.sub.1-C.sub.4)-alkoxy)carbonyl, and formyl; or
[0019] 10) (C.sub.2-C.sub.5)-alkenyl, which is unsubstituted or is
substituted by a substituent chosen from phenyl, cyano,
hydroxycarbonyl, and ((C.sub.1-C.sub.4)-alkoxy)carbonyl; or
[0020] 11) (C.sub.2-C.sub.5)-alkynyl, which is unsubstituted or is
substituted by a substituent chosen from phenyl and
(C.sub.1-C.sub.4)-alkoxy; or
[0021] 12) 5-membered or 6-membered monocyclic heteroaryl having
one or two identical or different ring heteroatoms chosen from
oxygen, sulfur, and nitrogen; or
[0022] 13) --S(O).sub.m-phenyl which is unsubstituted or is
substituted by one or two identical or different substituents
chosen from halogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy, and trifluoromethyl;
[0023] R(2) is hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.7)-cycloalkyl, but is not hydrogen if Z is
oxygen;
[0024] the residues R(3), which are all independent of one another
and can be identical or different, are hydrogen or
(C.sub.1-C.sub.3)-alkyl;
[0025] A is one of the following residues: 4
[0026] in which the free bond via which the residue is bonded to
the amino group in the formula (I) is represented by the symbol
[0027] X is oxygen or sulfur;
[0028] Y is --(CR(3).sub.2).sub.n--;
[0029] Z is NH or oxygen;
[0030] m is 0, 1 or 2;
[0031] n is 1, 2, 3 or 4;
[0032] in all their stereoisomeric forms and mixtures thereof in
all ratios, and their physiologically tolerable salts.
[0033] If groups, residues, substituents or variables can occur
several times in the compounds of the formula (I), they can all
independently of one another have the meanings indicated and can in
each case be identical or different.
[0034] The term alkyl denotes straight-chain or branched saturated
hydrocarbon residues. This also applies to groups derived therefrom
such as, for example, alkoxy, alkoxycarbonyl or the residue
--S(O).sub.m-alkyl. Examples of alkyl residues Include methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,
tert-butyl, n-pentyl, 1-methyl-butyl, isopentyl, neopentyl,
tert-pentyl, n-hexyl or isohexyl. Examples of alkoxy include
methoxy, ethoxy, propoxy such as n-propoxy and isopropoxy, butoxy
such as n-butoxy, isobutoxy and tert-butoxy, etc. The same applies
correspondingly to substituted alkyl residues, for example
phenylalkyl residues, and to divalent alkyl residues (alkanediyl
residues), in all of which the substituents or the bonds, via which
the residues are bonded to the neighboring groups, can be situated
in any desired positions. Examples of alkyl residues of this type,
which are bonded to two neighboring groups, include --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--, --CH.sub.2--CH.sub.2--,
--CH(CH.sub.3)--CH.sub.2--- , --CH.sub.2--CH(CH.sub.3)--,
CH.sub.2--CH.sub.2--CH.sub.2-- or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- all of which, inter
alia, can represent the group Y or can be present in a group
--O--(C.sub.1-C.sub.4)-alkyl which carries one substituent.
[0035] Alkenyl and alkynyl are straight-chain or branched,
monounsaturated or polyunsaturated hydrocarbon residues, in which
the double bonds and/or triple bonds can be situated in any desired
positions. For example, the residues alkenyl and alkynyl may
contain one double bond or one triple bond. Examples of alkenyl and
alkynyl include vinyl, prop-2-enyl (allyl), prop-1-enyl,
but-2-enyl, but-3-enyl, 3-methyl-but-2-enyl, pent-2,4-dienyl,
ethynyl, prop-2-ynyl (propargyl), prop-1-ynyl, but-2-ynyl and
but-3-ynyl. In substituted alkenyl residues and alkynyl residues
the substituents can be situated in any desired positions.
[0036] Examples of cycloalkyl include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and cycloheptyl all of which can also be
substituted by one or more, for example one, two, three or four,
identical or different (C.sub.1-C.sub.4)-alkyl residues, for
example methyl residues.
[0037] Halogen is fluorine, chlorine, bromine, or iodine, for
example, chlorine or fluorine.
[0038] In substituted phenyl residues the substituents can be
situated in any desired positions. In monosubstituted phenyl
residues the substituent can be situated in the 2-position, the
3-position, or the 4-position. In disubstituted phenyl residues the
substituents can be situated in 2,3-position, 2,4-position,
2,5-position, 2,6-position, 3,4-position or 3,5-position. If a
phenyl residue carries a further phenyl residue as a substituent,
then this second phenyl residue can also be unsubstituted or can be
substituted by the substituents indicated for the first phenyl
residue, apart from a phenyl residue.
[0039] The heteroaryl residues, which are derived from monocyclic
5-membered or 6-membered aromatic ring systems, can also be
regarded as residues derived from cyclopentadienyl or phenyl by
replacement of one or two CH groups and/or CH.sub.2 groups by S, O,
N, NH (or N carrying a substituent such as, for example,
N--CH.sub.3), the aromatic ring system being retained or an
aromatic ring system being formed. In addition to the one or two
ring heteroatoms, they contain three to five ring carbon atoms.
Examples of heteroaryl include furyl, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,3-oxazolyl, 1,2-oxazolyl, 1,3thiazolyl,
1,2thiazolyl, pyridyl, pyrazinyl, pyrimidyl or pyridazinyl. A
heteroaryl residue can be bonded via any ring carbon atom. For
example, a thienyl residue can be present as a 2-thienyl residue or
3-thienyl residue, a furyl residue as a 2-furyl residue or 3furyl
residue, a pyridyl residue as a 2-pyridyl residue, 3-pyridyl
residue or 4-pyridyl residue. A residue derived from 1,3-thiazole
or from imidazole can be bonded via the 2-position, the 4-position,
or the 5-position. Suitable nitrogen heterocycles can also be
present as N-oxides or as quaternary salts with an anion derived
from a physiologically tolerable acid as counter ion. Pyridine
rings can thus also be present, for example, as pyridine
N-oxides.
[0040] A tetrahydrofuranyl residue can be bonded via the 2-position
or the 3-position, a tetrahydropyranyl residue via the 2-position,
the 3-position or the 4-position. Examples of tetrahydrofuranyl and
tetrahydropyranyl residues include tetrahydrofuran-2-yl and
tetrahydropyran-2-yl.
[0041] Another embodiment of the present invention comprises all
stereoisomeric forms of the compounds of the formula(I). Asymmetric
centers present in the compounds of the formula (I) can all
independently of one another have the S configuration or the R
configuration. The invention includes all possible enantiomers and
diastereomers, as well as mixtures of two or more stereoisomeric
forms, for example mixtures of enantiomers and/or diastereomers, in
all ratios. Enantiomers, for example, thus are a subject of the
invention in enantiomerically pure form, as levorotatory as well as
dextrorotatory antipode, in the form of the racemate and in the
form of mixtures of the two enantiomeric forms in all ratios. In
the presence of cis/trans isomerism or E/Z isomerism, the cis form,
the trans form, the E form, the Z form and mixtures of these forms
in all ratios are another subject of the invention. Individual
stereoisomers can be prepared, if desired, by resolution of a
mixture according to customary methods, for example by
chromatography or crystallization, or by use of stereochemically
uniform starting substances in the synthesis, or by stereoselective
reactions. If appropriate, a derivatization can be carried out
before separation of stereoisomers. The separation of a
stereoisomer mixture can be carried out at the stage of the
compounds of the formula (I) or at the stage of an intermediate in
the course of the synthesis. The invention also comprises all
tautomeric forms of the compounds of the formula (I).
[0042] Physiologically tolerable salts of the compounds of the
formula (I) include nontoxic salts or pharmaceutically utilizable
salts. They can contain inorganic or organic salt components. Such
salts can be prepared, for example, from compounds of the formula
(I) that contain one or more acidic groups, and nontoxic inorganic
or organic bases. Possible bases include, for example, suitable
alkali metal compounds or alkaline earth metal compounds, such as
sodium hydroxide or potassium hydroxide, or ammonia or organic
amino compounds or quaternary ammonium hydroxides. Reactions of
compounds of the formula (I) with bases for the preparation of the
salts are in general carried out according to customary procedures
in a solvent or diluent. On account of the physiological and
chemical stability, advantageous salts in the presence of acidic
groups include in many cases sodium, potassium, magnesium or
calcium salts or ammonium salts that can carry one or more organic
residues on the nitrogen. Salt formation on the nitrogen atom of
the benzenesulfonamide group in this case leads to compounds of the
formula (II), 5
[0043] in which A, R(1), R(2), X, Y, and Z have the meanings
indicated above and the cation M, for example, is an alkali metal
ion or an equivalent of an alkaline earth metal ion, for example
the sodium, potassium, magnesium, or calcium ion, or the
unsubstituted ammonium ion or an ammonium ion having one or more
organic residues. An ammonium ion representing M can, for example,
also be the cation that is obtained from an amino acid, for
instance a basic amino acid such as, for example, lysine or
arginine, by protonation.
[0044] Compounds of the formula (I) that contain one or more basic,
i.e. protonatable, groups, can be present and can be used according
to the invention in the form of their acid addition salts with
physiologically tolerable inorganic or organic acids, for example
as salts with hydrogen chloride, phosphoric acid, sulfuric acid or
organic carboxylic acids or sulfonic acids such as, for example,
p-toluenesulfonic acid, acetic acid, tartaric acid, benzoic acid,
fumaric acid, maleic acid, citric acid etc. Acid addition salts can
also be obtained from the compounds of the formula (I) according to
customary processes known to the person skilled in the art, for
example by combination with an organic or inorganic acid in a
solvent or diluent. If the compounds of the formula (I)
simultaneously contain acidic and basic groups in the molecule, the
present invention also comprises internal salts or betaines
(zwitterions), in addition to the salt forms described. The present
invention also comprises all salts of the compounds of the formula
(I) that, because of low physiological tolerability, are not
directly suitable for use in pharmaceuticals but can be used, for
example, as intermediates for chemical reactions or for the
preparation of physiologically tolerable salts, for example by
anion exchange or cation exchange.
[0045] The present invention furthermore comprises all solvates of
compounds of the formula (I), for example hydrates or adducts with
alcohols, and also derivatives of the compounds of the formula (I)
such as, for example, esters and amides of acid groups, and
prodrugs and active metabolites of compounds of the formula
(I).
[0046] In one embodiment of the present invention, the acyl residue
A is a quinoline-3-carbonyl residue. The residue A--NH-- contained
in the respective compounds, which is bonded to the group Y in the
formula (I), can be designated, for example, as a
3-quinolinecarboxamido residue or a quinoline-3-carbonylamino
residue. In a further embodiment of the present invention, the acyl
residue A is a 1-cyclohex-1-enecarbonyl residue. The residue
A--NH-- contained in the respective compounds, which is bonded to
the group Y in the formula 1, can be designated, for example, as a
1-cyclohex-1-enecarbonylamino residue or a
1-cyclohex-1-enecarboxamido residue (or also as a
cyclohex-1-enecarboxamido residue). In a further embodiment of the
present invention, the acyl residue A is a 3-methylbut-2-enoyl
residue. The residue A--NH-- contained in the respective compounds,
which is bonded to the group Y in the formula 1, can be designated,
for example, as a 3-methylbut-2-eneamido residue or a
3-methylbut-2-enoylamino residue (or also as
3,3-dimethylacryloylamino residue).
[0047] In one embodiment of the invention, in compounds of the
formula (I) Z is oxygen and X is oxygen.
[0048] Y may be the residue --(CR(3).sub.2).sub.n-- in which the
residues R(3) are hydrogen or methyl, for example, hydrogen. n may
be 2 or 3, for example, 2. An example of the group Y is the group
--CH.sub.2--CH.sub.2--.
[0049] Z may be NH. Examples of compounds of the formula (I)
include the benzenesulfonamide derivatives of the formula (Ia),
6
[0050] in all their stereoisomeric forms and mixtures thereof in
all ratios, and their physiologically tolerable salts. A subgroup
of these compounds is formed by the benzenesulfonylthiourea
derivatives of the formula(Ib), 7
[0051] in all their stereoisomeric forms and mixtures thereof in
all ratios, and their physiologically tolerable salts, another
subgroup is composed by the benzenesulfonylurea derivatives of the
formula(Ic), 8
[0052] in all their stereoisomeric forms and mixtures thereof in
all ratios, and their physiologically tolerable salts. In the
formulae (Ia), (Ib), and (Ic) the residues A, R(1), R(2), X and Y
have the meanings indicated above. Another subgroup of the
compounds according to the invention is formed by compounds of the
formula (I) in which X is oxygen, Z is NH, and R(2) is methyl.
[0053] Examples of a (C.sub.1-C.sub.4)-alkyl residue representing
R(1) include methyl, ethyl, and isopropyl.
[0054] An unsubstituted --O--(C.sub.1-C.sub.4)-alkyl residue
representing R(1) may include, for example, one of the residues
methoxy, ethoxy, and propoxy for example methoxy or ethoxy. The
alkyl group in a substituted --O--(C.sub.1-C.sub.4)-alkyl residue
representing R(1) may include, for example, a methyl group or an
ethyl group that is substituted in the 2-position. A
fluorine-substituted --O--(C.sub.1-C.sub.4)-alkyl residue
representing R(1) may include, for example, one of the residues
trifluoromethoxy, 2-fluoroethoxy and 2,2,2-trifluoroethoxy, for
example trifluoromethoxy. A substituted
--O--(C.sub.1-C.sub.4)-alkyl residue representing R(1), that
carries a substituent other than fluorine atoms, may carry, for
example, one of the substituents ((C.sub.1-C.sub.4)-alkyl)-
carbonylamino, (C.sub.1-C.sub.4)-alkylamino,
di((C.sub.1-C.sub.4)-alkyl)am- ino, piperidin-1-yl, morpholin-4-yl,
tetrahydrofuranyl, tetrahydropyranyl, phenoxy, and phenyl, for
example morpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl,
phenoxy, and phenyl, including tetrahydrofuranyl,
tetrahydropyranyl, and phenyl, where the phenyl group and the
phenoxy group can in each case be unsubstituted or substituted as
indicated, for example unsubstituted. Examples of
--O--(C.sub.1-C.sub.4)-alkyl residues that carry a substituent
other than fluorine atoms include tetrahydrofuran-2-ylmethoxy,
tetrahydropyran-2-ylmethoxy, 2-(morpholin-4-yl)ethoxy,
2-phenoxyethoxy, benzyloxy and 2-phenylethoxy, for example
tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy and
benzyloxy.
[0055] In one embodiment of the invention, in the residue
--O--(C.sub.1-C.sub.4)-alkyl-E(1)-(C.sub.1-C.sub.4)-alkyl-D(1)
representing R(1), the groups E(1), E(2) and E(3) that can be
present therein are oxygen. D(1) may be, for example, hydrogen. If
D(1) has a meaning other than hydrogen, D(2) may be, for example,
hydrogen. Examples of the residue
--O--(C.sub.1-C.sub.4)-alkyl-E(1)-(C.sub.1-C.sub.4)-alkyl-- D(1)
include --O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl and
--O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub-
.4)-alkyl, for instance
O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-al- kyl, such as
2-methoxyethoxy, 2-ethoxyethoxy, and 2-(2-methoxyethoxy)ethox- y,
for example 2-methoxyethoxy and 2-ethoxyethoxy.
[0056] In the residue
--O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-al- kyl
representing R(1) in which the terminal alkoxy group, i.e. the
alkoxy group that is not directly bonded to the benzene ring in the
formula (I), is substituted by fluorine atoms, the
fluorine-substituted alkoxy group may be one of the groups
trifluoromethoxy and 2,2,2-trifluoroethoxy. Examples of a
fluorine-substituted --O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub-
.1-C.sub.4)-alkyl residue representing R(1) include
--O--(C.sub.1-C.sub.4)-alkyl-O--CF.sub.3 or
--O--(C.sub.1-C.sub.4)-alkyl-- O--CH.sub.2--CF.sub.3, for example
2-(trifluoromethoxy)ethoxy or 2-(2,2,2-trifluoroethoxy)ethoxy.
[0057] An example of a residue --O--(C.sub.2-C.sub.4)-alkenyl
representing R(1) may be allyloxy.
[0058] A residue --O-phenyl representing R(1) may be, for example,
unsubstituted or monosubstituted phenoxy, for example, phenoxy that
is unsubstituted or substituted in the 4-position, including
unsubstituted phenoxy, 4-methylphenoxy, 4-methoxyphenoxy,
4-fluorophenoxy or 4-trifluoromethylphenoxy.
[0059] Halogen representing R(1) may be, for example, bromine or
iodine.
[0060] A phenyl residue representing R(1) may be, for example,
unsubstituted or monosubstituted phenyl, including phenyl that is
unsubstituted or substituted in the 4-position, for instance,
phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, or
4-trifluoromethylphenyl, for example, unsubstituted phenyl.
[0061] A residue (C.sub.2-C.sub.5)-alkenyl representing R(1) may
be, for example, allyl.
[0062] A residue (C.sub.2-C.sub.5)-alkynyl representing R(1) may
be, for example, ethynyl.
[0063] A heteroaryl residue representing R(1) may contain, for
example, one ring heteroatom, and may be for instance, a pyridyl
residue, thienyl residue or fur residue, including the residues
2-pyridyl, 3-pyridyl, 2-thienyl and 2-furyl.
[0064] A residue --S(O).sub.m-phenyl representing R(1) may be, for
example, unsubstituted or monosubstituted --S(O).sub.m-phenyl, for
instance unsubstituted --S(O).sub.m-phenyl such as the
unsubstituted residue --S-phenyl.
[0065] m may be, for example, 0 or 2, for instance 0.
[0066] In one embodiment of the invention R(1) is
[0067] 1) methyl, ethyl, or isopropyl; or
[0068] 2) methoxy, ethoxy, propoxy, trifluoromethoxy,
2-fluoroethoxy, or 2,2,2-trifluoroethoxy; or
[0069] 3) tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy,
2-(morpholin-4-yl)ethoxy, 2-phenoxyethoxy, benzyloxy, or
2-phenylethoxy; or
[0070] 4) 2-methoxyethoxy, or 2-ethoxyethoxy; or
[0071] 5) 2-(trifluoromethoxy)ethoxy, or
2-(2,2,2-trifluoroethoxy)ethoxy; or
[0072] 6) allyloxy; or
[0073] 7) phenoxy, 4-fluorophenoxy, 4-methylphenoxy,
4-methoxyphenoxy, or 4-trifluoromethylphenoxy; or
[0074] 8) bromine or iodine; or
[0075] 9) phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl,
or 4-trifluoromethylphenyl; or
[0076] 10) allyl; or
[0077] 11) ethynyl; or
[0078] 12) furyl, thienyl, or pyridyl; or
[0079] 13) --S-phenyl.
[0080] In another embodiment of the invention R(1) includes those
residues that are bonded via an oxygen atom to the benzene ring
carrying the group R(1), and optionally substituted phenyl residue
or heteroaryl residues. For example, R(1) may be one of the
residues methoxy, ethoxy, trifluoromethoxy, 2-methoxyethoxy,
2-ethoxyethoxy, 2-(trifluoromethoxy)ethoxy,
2-(2,2,2-trifluoroethoxy)ethoxy, tetrahydrofuran-2-ylmethoxy,
tetrahydropyran-2-ylmethoxy, or benzyloxy.
[0081] If Z is NH, R(2) may be, for example, hydrogen,
(C.sub.1-C.sub.4)-alkyl or cyclohexyl, including
(C.sub.1-C.sub.4)-alkyl or cyclohexyl, such as methyl, ethyl,
isopropyl, or cyclohexyl, for example methyl, ethyl or isopropyl. A
specific subgroup of compounds of the formula (I) in which Z is NH
is formed by compounds in which R(2) is hydrogen or methyl. If Z is
oxygen, R(2) may be, for example, (C.sub.1-C.sub.4)-alkyl. In one
embodiment of the invention R2 is methyl.
[0082] More examples of the compounds of the formula (I) include
those in which one or more of the residues present therein have the
meanings exemplified above. All combinations of exemplified
substituent definitions are also a subject of the present
invention. Another embodiment of the invention includes all
stereoisomeric forms of the compounds of the formula (I)
exemplified above and mixtures thereof in all ratios, and their
physiologically tolerable salts.
[0083] Thus, for example, a group of exemplified compounds may be
formed by those compounds of the formula (I) in which Z is NH, X is
sulfur and R(2) is methyl, and the other residues have the general
or exemplified meanings indicated above, in all their
stereoisomeric forms and mixtures thereof in all ratios, and their
physiologically tolerable salts.
[0084] Another subgroup of the compounds of the invention is formed
by those compounds of the formula (I) in which
[0085] Y is --CH.sub.2--CH.sub.2--;
[0086] R(2) is methyl, ethyl, isopropyl or cyclohexyl;
[0087] and R(1), A, X and Z have the general or exemplified
meanings indicated above, in all their stereoisomeric forms and
mixtures thereof in all ratios, and their physiologically tolerable
salts. Examples of more subgroups of the compounds of the invention
include those compounds formed by compounds of the formula (I) in
which Z is NH and/or X is sulfur. One more subgroup of the
compounds of the invention is formed by compounds in which R(2) is
methyl.
[0088] Another embodiment of the invention includes compounds of
the formula (I) in which
[0089] R(1) is methoxy, ethoxy, 2-methoxyethoxy, 2-ethoxyethoxy,
trifluoromethoxy, 2-(trifluoromethoxy)ethoxy,
2-(2,2,2-trifluoroethoxy)et- hoxy, tetrahydrofuranylmethoxy,
tetrahydropyranylmethoxy, or benzyloxy;
[0090] R(2) is methyl, ethyl, or isopropyl;
[0091] Z is NH;
[0092] and A, X and Y have the general or exemplified meanings
indicated above, in all their stereoisomeric forms and mixtures
thereof in all ratios, and their physiologically tolerable
salts.
[0093] Another embodiment of the present invention relates to
processes for the preparation of the compounds of the formula (I),
which are illustrated below and according to which the compounds of
to the invention are obtainable.
[0094] Compounds of the formula (I) in which X is sulfur and Z is
NH, i.e. benzenesulfonylthioureas of the formula(Ib), 9
[0095] in which A, R(1), R(2), and Y have the abovementioned
meanings, can be prepared, for example, by reacting
benzenesulfonamides of the formula(III), 10
[0096] in which A, R(1), and Y have the abovementioned meanings, in
an inert solvent or diluent with a base and with an
R(2)-substituted isothiocyanate of the formula (IV)
R(2)--N.dbd.C.dbd.S IV
[0097] in which R(2) has the meanings indicated above. Suitable
bases include, for example, alkali metal or alkaline earth metal
hydroxides, hydrides, amides or alkoxides, such as sodium
hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride,
potassium hydride, calcium hydride, sodium amide, potassium amide,
sodium methoxide, sodium ethoxide, potassium tert-butoxide, or
quaternary ammonium hydroxides. The reaction of the compound of the
formula (Ill) with the base can initially be carried out in a
separate step and the resulting salt of the formula (V), can also
be intermediately isolated, if desired. 11
[0098] In the compounds of formula (V), A, R(1) and Y have the
abovementioned meanings and the cation M.sup.1 is an alkali metal
ion, for example a sodium ion or potassium ion, or an equivalent of
an alkaline earth metal ion, for example of a magnesium ion or
calcium ion, or an ammonium ion which is inert under the reaction
conditions, for example a quaternary ammonium ion. The salt of the
formula (V), however, can also be produced in situ from the
compound of the formula (III) and reacted directly with the
isothiocyanate of the formula (IV). Suitable inert solvents for the
reaction include, for example, ethers such as tetrahydrofuran
(THF), dioxane, ethylene glycol dimethyl ether (DME) or diethylene
glycol dimethyl ether (diglyme); ketones such as acetone or
butanone, nitriles such as acetonitrile, nitro compounds such as
nitromethane, esters such as ethyl acetate; amides such as
dimethylformamide (DMF), N-methylpyrrolidone (NMP), or
hexamethylphosphoric triamide (HMPT), sulfoxides such as
dimethylsulfoxide (DMSO); or hydrocarbons such as benzene, toluene
or xylenes. Furthermore, mixtures of these solvents with one
another are also suitable. The reaction of the compound of the
formula (III) or (V) with the compound of the formula (IV) may be,
for example, carried out at temperatures from room temperature to
about 150.degree. C., including temperatures ranging from room
temperature to about 100.degree. C.
[0099] Compounds of the formula (I) in which X is oxygen and Z is
NH, i.e. benzenesulfonylureas of the formula (Ic), 12
[0100] in which A, R(1), R(2) and Y have the abovementioned
meanings, can be prepared, for example, by reacting, analogously to
the synthesis of the thiourea derivatives of the formula (Ib)
described above, benzenesulfonamides of the formula (III) or their
salts of the formula (V) in an inert solvent or diluent with a base
and with an R(2)-substituted isocyanate of the formula (VI)
R(2)--N.dbd.C.dbd.O VI
[0101] in which R(2) has the meanings indicated above. The above
illustrations of the reaction with isothiocyanates correspondingly
apply to the reaction with the isocyanates.
[0102] Benzenesulfonylureas of the formula (Ic) can also be
prepared from the benzenesulfonamides of the formula (III) or their
salts of the formula (V) by reaction with R(2)-substituted
2,2,2-trichloroacetamides of the formula (VII),
Cl.sub.3C--CO--NH--R(2) VII
[0103] in which R(2) has the meanings indicated above, in the
presence of a base in an inert, high-boiling solvent such as, for
example, DMSO.
[0104] Benzenesulfonylureas of the formula (Ic) can also be
prepared by means of a conversion reaction (desulfurization) from
the corresponding benzenesulfonylthioureas of the formula (Ib). The
replacement of the sulfur atom in the thiourea group of the
compounds of the formula (Ib) by an oxygen atom can be carried out,
for example, with the aid of oxides or salts of heavy metals or by
use of oxidants such as hydrogen peroxide, sodium peroxide, or
nitrous acid.
[0105] Benzenesulfonylureas and -thioureas of the formulae (Ic) and
(Ib) can also be prepared by reaction of amines of the formula
R(2)--NH.sub.2. in which R(2) has the abovementioned meanings, with
benzenesulfonyl isocyanates and isothiocyanates of the formula
(VIII) 13
[0106] in which A, R(1), X and Y have the abovementioned meanings.
The sulfonyl isocyanates of the formula (VIII) (X=oxygen) can be
obtained from the benzenesulfonamides of the formula (III)
according to customary methods, for example using phosgene. The
sulfonyl isothiocyanates of the formula (VIII) (X=sulfur) can be
prepared by reaction of the sulfonamide of the formula III with
alkali metal hydroxides and carbon disulfide in an organic solvent,
such as DMF, DMSO, or NMP. The di-alkali metal salt of the
sulfonyldithiocarbamic acid obtained here can be reacted in an
inert solvent using a slight excess of phosgene or of a phosgene
substitute such as triphosgene or using a chloroformic acid ester
(2 equivalents) or using thionyl chloride. The solution of the
sulfonyl iso(thio)cyanate of the formula (VIII) obtained can be
reacted directly with the appropriately substituted amine of the
formula R(2)--NH.sub.2 or, if compounds of the formula (I) are to
be prepared in which R(2) is hydrogen, can be reacted with
ammonia.
[0107] Correspondingly, starting from benzenesulfonyl
iso(thio)cyanates of the formula (VIII), by addition of alcohols of
the formula R(2)--OH in which R(2) has the abovementioned meanings
with the exception of hydrogen, compounds of the formula (I) can be
prepared in which Z is oxygen, i.e. the benzenesulfonylurethane
derivatives of the formula (Ih), 14
[0108] in which A, R(1), R(2), X and Y have the abovementioned
meanings, but R(2), as mentioned, is not hydrogen. Compounds of the
formula (Ih) can also be prepared, for example, by reacting,
analogously to the syntheses described above, benzenesulfonamides
of the formula (III) or their salts of the formula (V) in an inert
solvent, for example a high-boiling ether, with reactive carbonic
acid derivatives, for example with chloroformic acid esters of the
formula Cl--CO--OR(2) or pyrocarbonic acid diesters of the formula
(R(2)O--C(.dbd.O)).sub.2O in which R(2) has the abovementioned
meanings with the exception of hydrogen. Starting from the
compounds of the formula (Ih) in which X is oxygen, compounds of
the formula Ic are in turn obtainable by reaction with the
appropriate amine of the formula R(2)--NH.sub.2 in an inert,
high-boiling solvent, for example toluene, at temperatures up to
the boiling point of the respective solvent.
[0109] The benzenesulfonamides of the formula (III) as the starting
compounds for the processes for the synthesis of the
benzenesulfonamide derivatives of the formula (I) can be prepared
according to or analogously to known methods such as are described
in the literature, for example in standard works like Houben-Weyl,
Methoden der Organischen Chemie [Methods of Organic Chemistry],
Georg Thieme Verlag, Stuttgart, and Organic Reactions, John Wiley
& Sons, Inc., New York, and in the patent documents indicated
above, the relevant parts of which are hereby incorporated by
reference, if necessary with appropriate adjustment of the reaction
conditions as is familiar to the person skilled in the art. Use can
also be made in this case of variants that are known per se but not
illustrated here in greater detail. In the synthesis, it may also
be appropriate to temporarily block functional groups which would
react in an undesired manner or give rise to side reactions by
protective groups, or to employ them in the form of precursor
groups which are only later converted into the desired groups.
Strategies of this type are known to the person skilled in the art.
Starting substances can, if desired, also be formed in situ in such
a way that they are not isolated from the reaction mixture, but
immediately reacted further.
[0110] Thus it is possible, for example, to react p-substituted
benzene derivatives of the formula (IX), 15
[0111] in which Y has the abovementioned meanings and R(0) is, for
example, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy,
bromine, or nitro, with trifluoroacetic anhydride in the presence
of pyridine in an inert solvent such as, for example, THF to give
compounds of the formula (X), 16
[0112] in which Y and R(0) have the meanings indicated above.
[0113] Starting from the compounds of the formula (X) in which R(0)
is nitro, it is possible by means of reduction of the nitro group
using a reductant such as, for example, SnCl.sub.2.times.2 H.sub.2O
in an inert solvent such as ethyl acetate, diazotization of the
resulting amino group and subsequent reaction of the intermediate
diazonium compound according to processes known per se, such as are
described, for example, in Larock, Comprehensive Organic
Transformations, VCH, 1989, for example by reaction with potassium
iodide for the preparation of the iodo compounds, to obtain the
corresponding p-halogen-substituted compounds of the formula (XI),
17
[0114] in which Y has the meanings indicated above and Hal is
halogen.
[0115] The compounds of the formula (XI) and the compounds of the
formula (X) in which R(0) is (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy or bromine, which are collectively
designated as compounds of the formula(XII), 18
[0116] in which Y has the meanings indicated above and R(1a) is
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy or halogen, can
be converted in a known manner into the benzene sulfonamides of the
formula(XIII), 19
[0117] in which Y and R(1a) have the meanings mentioned. The
preparation of the sulfonamides of the formula (XIII) from the
compounds of the formula (XII) can be carried out in one, two or
more steps. Examples include processes in which the acylamines of
the formula (XII) are first converted by means of electrophilic
reagents in the presence or absence of inert solvents or diluents
at temperatures from about -20.degree. C. to about 120.degree. C.,
including temperatures from about 0.degree. C. to about 100.degree.
C., into the 2,5-substituted benzenesulfonic acids or their
derivatives such as, for example, the sulfonic acid halides. For
this, it is possible, for example, to carry out sulfonations using
sulfuric acids or oleum, or halosulfonations using halosulfonic
acids such as chlorosulfonic acid, or reactions with sulfuryl
halides in the presence of anhydrous metal halides, or reactions
with thionyl halides in the presence of anhydrous metal halides
with subsequent oxidations, carried out in a known manner, to give
sulfonyl chlorides. If sulfonic acids are the primary reaction
products, these can be converted into sulfonic acid halides either
directly or after treatment with amines such as, for example,
triethylamine or pyridine, or with alkali metal or alkaline earth
metal hydroxides or with other suitable bases, in a manner known
per se by means of acid halides such as, for example, phosphorus
trihalides, phosphorus pentahalides, thionyl halides or oxalyl
halides. The conversion of the sulfonic acid derivatives into the
sulfonamides of the formula (XIII) is carried out in a manner known
from the literature. For example, sulfonyl chlorides are reacted
with aqueous ammonia in an inert solvent such as, for example,
acetone at temperatures from about 0.degree. C. to about
100.degree. C.
[0118] For the preparation of compounds of the formula (I) in which
R(1) is (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy or
halogen, the compounds of the formula (XIII) can be converted by
treatment with an acid such as, for example, hydrochloric acid or
sulfuric acid, if appropriate with addition of a polar organic
solvent such as methanol or ethanol, at temperatures from about
0.degree. C. up to the boiling point of the solvent, into the
compounds of the formula(XIV), 20
[0119] in which R(1a) is (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy or halogen and Y has the meaning indicated
above.
[0120] For the preparation of compounds of the formula (I) in which
R(1) is any of the other residues mentioned above, initially the
sulfonamide group in suitable compounds of the formula (XIII) can
be temporarily protected by conversion into the
N-(N,N-dimethylaminomethylene)sulfonamid- e group. For example,
starting from compounds of the formula (XIII) the
dimethylaminomethylene compounds of the formula (XV), 21
[0121] in which Y has the meanings mentioned and R(1b) is
(C.sub.1-C.sub.4)-alkoxy, bromine or iodine, can be prepared by
reacting the compounds of the formula(XIII), for example, with
N,N-dimethylformamide dimethyl acetal or reacting them with
N,N-dimethyl-formamide in the presence of dehydrating agents such
as thionyl chloride, phosphorus oxychloride or phosphorus
pentachloride.
[0122] The compounds of the formula (XV) in which R(1b) is
(C.sub.1-C.sub.4)-alkoxy can then be converted by ether cleavage
into the phenols of the formula (XVI) 22
[0123] in which Y is as defined above. This ether cleavage is
carried out, for example, by treatment of the compounds of the
formula (XV) in which R(1b) is methoxy with acids or with Lewis
acids such as boron trifluoride, boron trichloride, boron
tribromide, aluminum trichloride, for instance boron tribromide, or
their etherates, in an inert solvent such as, for example,
dichloromethane.
[0124] The phenols of the formula (XVI) obtained can be converted
into the compounds of the formula (XVII) 23
[0125] in which Y has the abovementioned meanings and R(1c) is one
of the residues
--O--(C.sub.1-C.sub.4)-alkyl-E(1)-(C.sub.1-C.sub.4)-alkyl-D(1),
fluorine-substituted
--O--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-al- kyl,
substituted --O--(C.sub.1-C.sub.4)-alkyl,
--O--(C.sub.2-C.sub.4)-alke- nyl, or --O-phenyl. This conversion is
carried out by means of an O-alkylation of the phenols of the
formula (XVI) using appropriately substituted halogen compounds
such as iodides or bromides or sulfonic acid esters such as
methanesulfonic acid esters, p-toluenesulfonic acid esters or
trifluoromethanesulfonic acid esters. The sulfonic acid esters are
obtainable from the correspondingly substituted alcohols of the
formula R(1c)--H according to standard processes, for example by
using methanesulfonyl chloride in an inert solvent in the presence
of a base such as potassium carbonate or cesium carbonate in the
case of the methanesulfonic acid esters. For example, with
(2-bromoethyl) methyl ether or benzyl bromide the compounds of the
formula (XVII) and thus the final compounds of the formula (I) are
obtained in which R(1c) and R(1), respectively, is 2-methoxyethoxy
or benzyloxy. The O-alkylation is in general carried out in the
presence of a base in an inert solvent at temperatures from about
0.degree. C. up to the boiling point of the solvent according to
processes known per se.
[0126] The preparation of compounds of the formula (XVII) in which
R(1c) is --O-phenyl can be carried out by means of an O-arylation
of the phenols of the formula (XVI) with phenylboronic acids, for
example with phenylboronic acid or with substituted phenylboronic
acids such as 4-methoxyphenylboronic acid, in the presence of
copper catalysts, for example copper(II) acetate. Analogous
reactions are described, for example, in Tetrahedron Lett. 39
(1998), 2937, the relevant disclosure of which is hereby
incorporated by reference.
[0127] Starting from the compounds of the formula (XV) in which
R(1b) is bromine or iodine, the compounds of the formula (XVIII)
24
[0128] can be obtained in which Y has the indicated meanings and
R(1d) is one of the residues (C.sub.1-C.sub.4)-alkyl, phenyl,
(C.sub.2-C.sub.5)-alkenyl, (C.sub.2-C.sub.5)-alkynyl, heteroaryl or
--S(O).sub.m-phenyl. The conversion into the compounds of the
formula (XVIII) can be carried out by means of palladium-catalyzed
Suzuki coupling using arylboronic acids, for example phenylboronic
acid, 4-methoxyphenylboronic acid, or 4-methylthiophenylboronic
acid, or heteroarylboronic acids, for example thienylboronic acid,
or by means of Stille coupling using trialkylstannanes, for example
tributylstannylfuran, trimethylstannylpyridine or
ethinyltributylstannane- . The Suzuki coupling is carried out in
the presence of palladium (II) acetate and triphenylphosphine or
tetrakis(triphenylphosphine)palladium and a base such as, for
example, cesium carbonate or potassium carbonate. Corresponding
reactions are described in the literature. The Stille coupling is
carried out analogously to literature procedures using
bis(triphenylphosphine)palladium(II) chloride as catalyst. The
preparation of suitable stannanes is described, for example, in
Tetrahedron 49 (1993) 3325, the relevant disclosure of which is
hereby incorporated by reference. The preparation of compounds of
the formula (XVIII) in which R(1d) is alkyl can be carried out by
means of Pd(0)-catalyzed Nikishi-Kumada coupling of the compounds
of the formula (XV) in which R(1b) is iodine with an appropriate
organozinc derivative in the presence of
1,1'-bis(diphenylphosphino)ferrocene, palladium(II) acetate and
copper(I) iodide as catalysts in an inert solvent. Corresponding
couplings are described, for example, in Synlett 1996, 473, the
relevant disclosure of which is hereby incorporated by
reference.
[0129] Compounds of the formula (XVIII) in which R(1d) is
--S-phenyl can be prepared, analogously to literature procedures,
from the compounds of the formula (XV) in which R(1b) is iodine by
means of a copper(I) iodide-catalyzed nucleophilic substitution
reaction, using the sodium salt of the appropriate thiophenol. The
thioether group introduced in this way, and just so thioether
groups in other positions of the molecule of the formula (I) or of
a synthetic intermediate, can be oxidized by standard processes to
the sulfoxide group or to the sulfone group, for example by using a
peracid such as m-chloroperbenzoic acid.
[0130] The subsequent removal of the dimethylaminomethylene group
and of the trifluoroacetyl group functioning as a sulfonamide
protective group and amino protective group, respectively, from the
compounds of the formula (XVII) and (XVIII) then leads to the
corresponding compounds having a H.sub.2N--Y group and
H.sub.2N--SO.sub.2 group which, together with the compounds of the
formula (XIV), are represented by the formula (XIX), 25
[0131] in which Y and R(1) have the meanings indicated above for
the formula(I). This removal of the protective groups can be
carried out either under basic or under acidic conditions. This
reaction may be carried out by treatment of the compounds of the
formula (XVII) and (XVIII) in an inert solvent, for example an
alcohol, with acids such as, for example, hydrochloric acid.
[0132] The benzenesulfonamides of the formula (XIX) are then
acylated using carboxylic acid derivatives of the formula A--OH, in
which the residue A has the meanings indicated above, to give the
acylaminoalkyl-substituted benzenesulfonamides of the formula
(III). The carboxylic acids of the formula A--OH are commercially
available or can be prepared according to literature procedures.
The acylation is in generally carried out by converting the
carboxylic acid firstly into a reactive derivative, for example by
reaction with N,N'-carbonyldiimidazol- e in an inert solvent such
as, for example, THF, dioxane or DMF, and subsequent reaction with
the amine of the formula(XIX), if appropriate in the presence of a
base such as triethylamine or pyridine. As reactive derivatives of
the carboxylic acids also the acid halides or the acid anhydrides,
for example, can be used. The reactions in this case may be carried
out at temperatures from about 0.degree. C. up to the boiling point
of the chosen solvent or diluent, including at room temperature.
The acylation of the amines of the formula (XIX) using the
carboxylic acids can also be carried out, for example, in the
presence of condensing agents such as, for example,
N,N'-dicyclohexylcarbodiimide,
O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TOTU) or
1-benzotriazolyloxy-tripyrrolidinophosphonium hexafluorophosphate
(PyBOP).
[0133] The steps described for the preparation of the compounds of
the formula (I) can also be carried out in another sequence.
Depending on the substituents to be introduced in the individual
steps, one or another variant may be more advantageous. Thus, for
example, the preparation of the compounds of the formula (III) in
which R(1) is one of the residues (C.sub.1-C.sub.4)-alkyl, phenyl,
(C.sub.2-C.sub.5)-alkenyl, (C.sub.2-C.sub.5)-alkynyl, heteroaryl or
--S(O).sub.m-phenyl, can also be carried out in such a way that
firstly a compound of the formula XIV in which R(1a) is iodine or
bromine is converted by coupling with a carboxylic acid derivative
and temporary protection of the sulfonamide group, as described
above, into a compound of the formula (XX), 26
[0134] in which A and Y are as defined for formula (I) and
Hal.sup.1 is iodine or bromine. From the compound of the formula
(XX), it is then possible by means of the Suzuki, Stille, or
Nikishi-Kumada couplings described above using the appropriate
abovementioned coupling components, to obtain the compounds of the
formula (XXI), 27
[0135] in which A, R(1d) and Y have the meanings indicated above.
The compounds of the formula (XXI) can then be converted into the
compounds of the formula III by removal of the sulfonamide
protective group according to the process described above.
[0136] The compounds of the invention inhibit ATP-sensitive
potassium channels and influence the action potential of cells, for
example, muscle cells. The compounds of the invention have a
normalizing action on a disturbed action potential, such as is
present, for example, in the case of ischemia, and are suitable,
for example, for the treatment and prophylaxis of disorders of the
cardiovascular system, including arrhythmias and their sequelae,
for example of ventricular fibrillation or sudden cardiac death.
The activity of the compounds of the invention can be demonstrated,
for example, in the model described below, in which the action
potential duration on the papillary muscle of the guinea pig is
determined.
[0137] In addition to their action on ATP-sensitive potassium
channels in the cardiac muscle cell, the compounds of the invention
also have an action on the peripheral and/or the central autonomic
nervous system. The compounds of the invention influence
ATP-sensitive potassium channels of the vagal nervous system and
have a stimulating action on the vagal nervous system, for example,
a stimulating action on the vagal nervous system of the heart due
to inhibition of ATP-sensitive potassium channels in the cardiac
nerve.
[0138] In the ideal case, an optimum interaction, adapted to the
particular situation, exists between the vagal (or parasympathetic)
nervous system (=depressing nervous system) and the sympathetic
nervous system (=stimulating nervous system). In the case of
disease, however, this interaction may be disturbed and a
dysfunction of the autonomic nervous system may be present, i.e. an
inequilibrium may exist between the activity of the vagal nervous
system and the activity of the sympathetic nervous system.
Sympathovagal inequilibrium is understood in general as meaning a
hyperactivity of the sympathetic (=stimulating) nervous system
and/or a hypoactivity of the vagal (=depressing) nervous system,
where the two parts of the nervous system can reciprocally
influence one another. In particular, it is known that a
hypoactivity of the vagal system can result in a hyperactivity of
the sympathetic system. To avoid damage to cells or organs of the
body due to overshooting biological or biochemical processes which
are stimulated by an excessively high activity of the sympathetic
nervous system, it is therefore attempted in such cases to
compensate for a sympathovagal inequilibrium, for example to
restore the normal vagal activity by eliminating a vagal
dysfunction or hypoactivity.
[0139] Examples of diseases that can be treated by eliminating a
vagal dysfunction and thus compensating for a harmful sympathovagal
inequilibrium, are organic heart diseases such as coronary heart
disease, cardiac insufficiency and cardiomyopathies. Damages to
health that result from an inequilibrium of the autonomic nervous
system when the dysfunction affects the heart include, for example,
weakening of the myocardial contractile force and fatal cardiac
arrhythmias. The importance of the autonomic nervous system for
sudden cardiac death in heart diseases was described, for example,
by P. J. Schwartz (The ATRAMI prospective study: implications for
risk stratification after myocardial infarction; Cardiac
Electrophysiology Review 2 (1998) 38) or T. Kinugawa et al.
(Altered vagal and sympathetic control of heart rate in left
ventricular dysfunction and heart failure; Am. J. Physiol. 37
(1995) R310). Experimental investigations with electrical
stimulation of the cardiac vagus or stimulating analogs of the
vagal transmitter acetylcholine, for example carbachol, confirm the
protective action of a vagal activation against fatal cardiac
arrhythmias (see, for example, E. Vanoli et al., Vagal stimulation
and prevention of sudden death in conscious dogs with a healed
myocardial infarction; Circ. Res. 68 (1991) 1471).
[0140] A sympathovagal inequilibrium, however, can also occur, for
example, as a result of a metabolic disorder, for example of
diabetes mellitus (see, for example, A. J. Burger et al., Short-
and long-term reproducibility of heart rate variability in patients
with long-standing type I diabetes mellitus; Am. J. Cardiol. 80
(1997) 1198). A hypoactivity of the vagal system can also
temporarily occur, for example in the case of oxygen deficiency,
for example oxygen deficiency of the heart, which leads to a
reduced secretion of vagal neurotransmitters, for example of
acetylcholine.
[0141] On account of the surprising ability of the compounds of the
invention to abolish a hypoactivity of the vagal system or to
restore the normal vagal activity, these compounds offer an
efficient possibility of reducing, eliminating or preventing
dysfunctions of the autonomic nervous system, including in the
heart, and their sequelae such as, for example, the disease
conditions mentioned. The efficacy of the compounds of the
invention in the abolition of dysfunctions of the autonomic nervous
system, for example of a vagal dysfunction of the heart, can be
demonstrated in the model of chloroform-induced ventricular
fibrillation in mice described below.
[0142] The compounds of the formula (I) and their physiologically
tolerable salts can be used in animals, such as mammals, including
humans, as pharmaceuticals on their own, in mixtures with one
another or in the form of pharmaceutical preparations. Mammals in
which the compounds of the invention can be used or tested are, for
example, monkeys, dogs, mice, rats, rabbits, guinea pigs, cats and
larger farm animals such as, for example, cattle and pigs. The
invention therefore also relates to the compounds of the formula
(I) and their physiologically tolerable salts and their prodrugs
for use as pharmaceuticals, and pharmaceutical preparations (or
pharmaceutical compositions) that contain an efficacious dose of at
least one compound of the formula (I) and/or of a physiologically
tolerable salt thereof and/or of a prodrug thereof as active
constituent and a pharmaceutically tolerable carrier, i.e. one or
more pharmaceutically acceptable vehicles and/or excipients
(additives). The invention furthermore relates to the use of the
compounds of the formula (I) and/or their physiologically tolerable
salts and/or their prodrugs for the treatment, including the
therapy and prophylaxis, of the syndromes mentioned above or below,
to their use for the production of pharmaceuticals for the
treatment, including therapy and prophylaxis, of the syndromes
mentioned above or below, and to methods for the treatment,
including the therapy and prophylaxis, of the syndromes mentioned
above or below which comprise administering an efficacious amount
of at least one compound of the formula (I) and/or a
physiologically tolerable salt and/or a prodrug thereof.
[0143] The pharmaceutical preparations can be intended for enteral
or parenteral use and may contain 0.5 to 90 percent by weight of at
least one compound of the formula (I) and/or its physiologically
tolerable salts and/or its prodrugs. The amount of active compound
of the formula (I) and/or its physiologically tolerable salts
and/or its prodrugs in the pharmaceutical preparations may range
from about 0.2 to about 1000 mg, including from about 0.2 to about
500 mg, and from about 1 to about 300 mg, per dose unit. The
pharmaceutical preparations can be prepared in a manner known per
se. For this, the compounds of the formula (I) and/or their
physiologically tolerable salts and/or their prodrugs are mixed
with one or more solid or liquid vehicles and/or excipients and, if
desired, with other pharmaceutical active compounds, for example
pharmaceutical active compounds having cardiovascular activity such
as, for example, calcium antagonists, ACE inhibitors or
.beta.-blockers, and brought into a suitable dose form and
administration form, which can then be used as a pharmaceutical in
human medicine or veterinary medicine.
[0144] Possible vehicles include organic and inorganic substances
that are suitable, for example, for enteral, for example oral or
rectal, administration, or for parenteral administration, for
example by intravenous, intramuscular or subcutaneous injection or
infusion, or for topical or percutaneous administration, and do not
react in an undesired manner with the compounds of the invention.
Examples of vehicles include water, vegetable oils, waxes, alcohols
such as ethanol, propanediol or benzyl alcohols, glycerol, polyols,
polyethylene glycols, polypropylene glycols, glyceryl triacetate,
gelatin, carbohydrates such as lactose or starch, stearic acid and
its salts such as magnesium stearate, talc, lanolin, petroleum
jelly, or mixtures of two or more vehicles, for example mixtures of
water with one or more organic solvents such as mixtures of water
with alcohols. Examples of pharmaceutical forms for oral and rectal
administration, include tablets, film-coated tablets, sugar-coated
tablets, granules, hard and soft gelatin capsules, suppositories,
solutions, including oily, alcoholic or aqueous solutions, syrups,
juices, drops, suspensions, and emulsions. Examples of
pharmaceutical forms for topical application include, ointments,
creams, pastes, lotions, gels, sprays, foams, aerosols, solutions,
and powders. As solvents for solutions including injection and
infusion solutions, for example water or alcohols such as ethanol,
isopropanol or 1,2-propanediol or their mixtures with one another
or with water, among others, can be used. Further possible
pharmaceutical forms include, for example, implants. The compounds
of the formula (I) and their physiologically tolerable salts can
also be lyophilized and the lyophilizates obtained used, for
example, for the production of injection preparations. Liposomal
preparations are also suitable, for example, for topical
application. As examples of excipients (or additives) which can be
present in the pharmaceutical preparations, glidants,
preservatives, thickeners, stabilizers, disintegrants, wetting
agents, agents for achieving depot effect, emulsifiers, salts (for
example for influencing the osmotic pressure), buffer substances,
colorants, flavorings, and aromatizers may be mentioned. If
desired, pharmaceutical preparations can also contain one or more
further active compounds and/or, for example, one or more
vitamins.
[0145] On account of their ability to inhibit ATP-sensitive
potassium channels, for example in the heart, and/or to decrease or
to eliminate an inadequate function of the vagal nervous system and
thereby a vagal dysfunction or a dysfunction of the autonomic
nervous system, for example in the heart, the compounds of the
formula (I) and their physiologically tolerable salts and prodrugs
are valuable pharmaceutical active compounds that are suitable not
only as antiarrhythmics and for the control and prevention of the
sequelae of arrhythmias, but also for treatment and prophylaxis in
other heart diseases or disorders of the cardiovascular system.
Examples of such diseases that may be mentioned include cardiac
insufficiency, cardiomyopathies, cardiac hypertrophy, coronary
heart disease, angina pectoris, ischemia, and vagal dysfunction of
the heart including, for example, vagal dysfunction of the heart in
diabetes mellitus. The compounds of the invention can generally be
employed in the treatment of diseases that are associated with a
dysfunction of the autonomic nervous system or a hypoactivity or
dysfunction of the vagal nervous system, for example in the heart,
or are caused by such a dysfunction or in whose treatment an
increase in or normalization of the activity of the vagal nervous
system is desired. The compounds of the invention can also be
employed in diseases that are characterized by oxygen deficiency
conditions, in cerebral vascular disorders, and in dysfunctions of
the autonomic nervous system, for example vagal dysfunction in the
heart, which occur as a result of a metabolic disorder such as, for
example, diabetes mellitus.
[0146] The compounds of the invention are used as antiarrhythmics
for the treatment of cardiac arrhythmias of very different origin,
including the prevention of sudden cardiac death due to arrhythmia.
Examples of arrhythmic disorders of the heart include
supraventricular arrhythmias such as, for example, atrial
tachycardia, atrial flutters, or paroxysomal supraventricular
arrhythmias, or ventricular arrhythmias such as ventricular
extrasystoles, including life-threatening ventricular tachycardia
and the particularly dangerous fatal ventricular fibrillation. They
are suitable, for example, in those cases where arrhythmias are the
result of constriction of a coronary vessel such as occur, for
example, in angina pectoris or during acute cardiac infarcts or as
a chronic result of a cardiac infarct. They are, therefore,
suitable for the prevention of sudden cardiac death in post-infarct
patients. Further syndromes in which arrhythmias of this type
and/or sudden cardiac death due to arrhythmia play a part include,
for example, cardiac insufficiency or cardiac hypertrophy as a
result of chronically raised blood pressure.
[0147] Moreover, the compounds of the invention are able to
positively influence decreased contractility of the heart and a
weakened myocardial contractile force. This can be a
disease-related decline in cardiac contractility, such as, for
example, in cardiac insufficiency, but includes also acute cases
such as heart failure in the case of shock. The compounds of the
formula (I) and their physiologically tolerable salts are suitable
for improving cardiac function. For example, in a heart
transplantation, under the influence of the compounds of the
invention, the heart can resume its capability faster and more
reliably after the operation has taken place. The same applies to
operations on the heart that necessitate temporarily stopping
cardiac activity by means of cardioplegic solutions.
[0148] Owing to the fact that the compounds of the invention, in
addition to their direct cardiac action, i.e. the effect on the
action potential of the cardiac muscle cells, also have an indirect
action on the nervous system of the heart or on the parts of the
nervous system acting on the heart, they can decrease or prevent
undesirable sequelae emanating from the nervous system or mediated
by the nervous system in the respective syndrome present. On
account of this, further damage to health such as a weakening of
the myocardial contractile force or in some cases fatal cardiac
arrhythmias such as ventricular fibrillation can be reduced or
avoided. Owing to the elimination or reduction of the dysfunction
of the autonomic nervous system, the compounds of the invention
have the effect that the weakened myocardial contractile force is
normalized again and that the cardiac arrhythmias that can lead to
sudden cardiac death do no longer develop. By selecting compounds
of the invention having a suitable profile of action with respect
to direct cardiac action (=direct effect on the action potential of
the cardiac muscle cells and on account of this a direct effect on
the contractile force and a direct antiarrhythmic effect) on the
one hand and the action on the cardiac nerves on the other hand, it
is efficiently possible with the aid of the compounds of the
invention to favorably influence heart diseases. Depending on the
syndrome present, it can also be advantageous in this case to
employ compounds of the invention that have only a relatively
slight direct cardiac effect and, on account of this, for example,
have only a relatively slight direct effect on the contractile
force of the heart or the formation of arrhythmias, but can improve
or normalize the myocardial contractile force or the cardiac rhythm
by means of the effect on the autonomic nervous system.
[0149] As used here, treatment includes therapy for a particular
disease, such as treating cardiac insufficiency. In this respect,
treatment can mean successfully eliminating the disease, reducing
the effects associated with it, and/or reducing its severity.
Treatment also includes prevention and prophylaxis of the onset of
a disease by treating patients falling into a risk group or
category for developing a particular disease or by treating
patients after a successful treatment to prevent reoccurrence of
the treated disease. Those skilled in the art can routinely
identify patients likely to present with a disease, thereby
qualifying as candidates for prevention therapy, because of factors
such as diet, habits (e.g., smoking), family history for the
disease, etc.
[0150] The dose of the compounds of the formula (I) or their
physiologically tolerable salts depends, as usual, on the
circumstances of the particular individual case and is adjusted by
the person skilled in the art according to the usual rules and
procedures. It depends, for example, on the specific compound of
the invention administered, its potency and duration of action, on
the nature and severity of the individual syndrome, on the sex,
age, weight and on the individual responsiveness of the human or
animal to be treated, on whether treatment is to be acute or
prophylactic or on whether further active compounds are
administered in addition to compounds of the invention. An
effective amount of a compound of the invention is an amount
sufficient to bring about a desired effect. For example, in the
context of inhibition of ATP-sensitive potassium channels, an
effective amount of a compound of the invention would constitute an
amount sufficient to inhibit ATP-sensitive potassium channels.
[0151] Normally, In the case of administration to an adult weighing
about 75 kg it is possible to manage with a dose that is about 0.1
mg to about 100 mg per kg per day, including doses from about 1 mg
to about 10 mg per kg per day (in each case in mg per kg of body
weight). The daily dose can be administered in the form of a single
oral or parenteral dose or divided into a number of individual
doses, for example two, three or four doses. The administration can
also be carried out continuously. If acute cases of cardiac
arrhythmias are treated, for example in an intensive care unit,
parenteral administration, for example by injection or by
intravenous continuous infusion, can be advantageous. A dose range
in critical situations then may be from about 1 to about 100 mg per
kg of body weight per day. Depending on individual behavior, it may
be necessary to deviate upward or downward from the doses
indicated.
[0152] Apart from being used as pharmaceutically active compounds
in human medicine and veterinary medicine, the compounds of the
invention can also be employed, for example, as auxiliaries for
biochemical investigations or as a scientific tool when a
respective effect on ion channels is intended, or for the isolation
or characterization of potassium channels. They can also be used
for diagnostic purposes, for example in in-vitro diagnoses of cell
samples or tissue samples. The compounds of the formula (I) and
their salts can furthermore be used as chemical intermediates for
the production of further pharmaceutical active compounds.
[0153] Other than in the operating examples, or where otherwise
indicated, all numbers expressing quantities of ingredients,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the present specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained by the present invention.
At the very least, and not as an attempt to limit the application
of the doctrine of equivalents to the scope of the claims, each
numerical parameter should be construed in light of the number of
reported significant digits and by applying ordinary rounding
techniques.
[0154] Notwithstanding that the numerical ranges and parameters
setting forth the broad scope of the invention are approximations,
the numerical values set forth in the specific examples are
reported as precisely as possible. Any numerical value, however,
inherently contain certain errors necessarily resulting from the
standard deviation found in their respective testing
measurements.
[0155] The invention is illustrated by the examples below, without
being restricted to these.
1 Abbreviations DCI Desorption chemical ionization DCM
Dichloromethane DMF Dimethylformamide EA Ethyl acetate ESI Electron
spray ionization FAB Fast atom bombardment M.p. Melting point h
Hour(s) min Minute(s) MS Mass spectrum RT Room temperature THF
Tetrahydrofuran
EXAMPLE 1
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-methoxyphenylsulfonyl]-3-methyl-t-
hiourea
[0156] 28
[0157] a) 2,2,2-Trifluoro-N-(2-(4-methoxyphenyl)ethyl)acetamide
[0158] 32.2 ml (0.23 mol) of trifluoroacetic anhydride were added
dropwise to a solution of 22.3 ml (0.15 mol) of
2-(4-methoxyphenyl)ethylamine and 24.7 ml (0.23 mol) of pyridine in
125 ml of absolute THF cooled to 5.degree. C., and the resulting
solution was stirred at RT for 3 h. The reaction solution was then
poured onto 750 ml of ice, and the precipitate deposited was
filtered off with suction and dried in a high vacuum at 40.degree.
C. 36.3 g of the title compound resulted as a beige solid.
[0159] M.p.: 74-77.degree. C.
[0160] R.sub.f (SiO.sub.2, EA/toluene 1:4)=0.62
[0161] MS (ESI); m/z=248 [M+H].sup.+
[0162] b)
2-Methoxy-5-(2-(2,2,2-trifluoroacetamido)ethyl)benzenesulfonamid-
e
[0163] 36.3 g (0.15 mol) of the compound of example 1a) were added
in portions to 200 ml of chlorosulfonic acid and the resulting
mixture was stirred at RT for 2 h. The reaction mixture was then
added dropwise to about 1.5 l of ice and the deposited precipitate
was filtered off with suction. The precipitate was dissolved in 100
ml of acetone, and the solution was treated with 250 ml of
concentrated ammonia solution with ice-cooling and stirring for 45
min. The reaction solution was then poured onto about 800 ml of
ice. Filtering off the deposited precipitate with suction and
drying it in a high vacuum yielded 30.4 g of the title compound as
a pale yellow solid.
[0164] M.p.: 160-161.degree. C.
[0165] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.51
[0166] MS (DCl): m/z=327 [M+H].sup.+
[0167] c) 5-(2-Aminoethyl)-2-methoxybenzenesulfonamide
[0168] A solution of 30.3 g (93.0 mmol) of the compound of example
1b) in 130 ml of 2N hydrochloric acid was heated to reflux for 12
h. The deposited precipitate was filtered off with suction,
dissolved in 70 ml of water, and the pH of the resulting solution
was adjusted to about 10 by addition of 2N sodium hydroxide
solution. After brief warming to 100.degree. C., the solution was
cooled in an ice bath and the deposited precipitate was filtered
off with suction. Drying of the precipitate in a high vacuum
yielded 13.7 g of the title compound as a beige solid.
[0169] M.p.: 180-181.degree.C.
[0170] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.02
[0171] MS (ESI): m/z=231 [M+H].sup.+
[0172] d)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-methoxybenzenesulfonamide
[0173] A solution of 500 mg (2.89 mmol) of 3-quinolinecarboxylic
acid in 20 ml of absolute THF was treated under an argon atmosphere
with 515 mg (3.18 mmol) of N,N'-carbonyldiimidazole and stirred at
RT for 3.5 h. The resulting solution was then treated successively
with 1.4 ml of triethylamine and 770 mg (2.89 mmol) of the compound
of example 1c) and stirred at RT for 20 h. The reaction solution
was then poured onto 20 ml of 1 N hydrochloric acid. The deposited
precipitate was filtered off, washed with a little water and dried
in a high vacuum. 508 mg of the title compound resulted as an
amorphous beige solid.
[0174] R.sub.f (SiO.sub.2, EA)=0.34
[0175] MS (ESI): m/z=386 [M+H].sup.+
[0176] e)
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-methoxyphenylsulfonyl]--
3-methyl-thiourea
[0177] A solution of 501 mg (1.30 mmol) of the compound of example
1d) and 178 mg (1.58 mmol) of potassium tert-butoxide in 9 ml of
absolute DMF was stirred at 80.degree. C. for 20 min. 1.61 ml of a
1 M solution of methyl isothiocyanate in absolute DMF were added
and the resulting solution was stirred at 80.degree. C. for 1 h.
The reaction solution was then poured onto 50 ml of 1 N
hydrochloric acid, and the deposited precipitate was filtered off
with suction and washed repeatedly with water. Drying of the
precipitate in a high vacuum yielded 188 mg of the title compound
as a white solid.
[0178] M.p.: 85.degree. C.
[0179] R.sub.f (SiO.sub.2, EA)=0.50
[0180] MS (ESI): m/z=459 [M+H].sup.+
EXAMPLE 2
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-methoxyethoxy)phenylsulfonyl]--
3-methyl-thiourea
[0181] 29
[0182] a)
N-Dimethylaminomethylene-2-methoxy-5-(2-(2-2,2-trifluoroacetamid-
o)ethyl)-benzenesulfonamide
[0183] 30.2 g (92.6 mmol) of the compound of example 1b) were
dissolved in 70 ml of absolute DMF, 14.0 ml (105.4 mmol) of
dimethylformamide dimethyl acetal were added, and the resulting
solution was stirred at RT for 3 h. It was concentrated to dryness,
and the residue was stirred with 100 ml of water and 100 ml of 5%
strength sodium hydrogensulfate solution. The crystalline
precipitate obtained was washed repeatedly with water and then
dried in a high vacuum. 29.6 g of the title compound resulted as a
white solid.
[0184] M.p.: 143-144.degree. C.
[0185] R.sub.f (SiO.sub.2, EA)=0.25
[0186] MS (DCl): m/z=382 [M+H].sup.+
[0187] b)
N-Dimethylaminomethylene-2-hydroxy-5-(2-(2,2,2-trifluoroacetamid-
o)ethyl)-benzenesulfonamide
[0188] 100 ml of a 1M solution of boron tribromide in DCM were
added dropwise over a period of 40 min at RT to a solution of 29.5
g (77.2 mmol) of the compound of example 2a) in 450 ml of DCM.
After stirring at RT for 5 h, the reaction mixture was treated with
150 ml of methanol and then with about 2 l of diisopropyl ether.
The deposited precipitate was filtered off with suction and dried
in a high vacuum. 32.7 g of the hydrobromide salt of the title
compound were obtained as a white solid.
[0189] M.p.: 160-161.degree. C.
[0190] R.sub.f (SiO.sub.2, EA)=0.52
[0191] MS (DCl): m/z=368 [M+H].sup.+
[0192] c)
N-Dimethylaminomethylene-2-(2-methoxyethoxy)-5-(2-(2,2,2-trifluo-
roacetamido)ethyl)benzenesulfonamide
[0193] A mixture of 9.1 g (2.03 mmol) of the compound of example
2b) and 7.1 g (50.8 mmol) of potassium carbonate in 50 ml of
absolute DMF was treated with 6.7 ml (71.7 mmol) of 2-bromoethyl
methyl ether and stirred at 70.degree. C. for 3 h. After adding a
further 6.7 ml of 2-bromoethyl methyl ether and stirring at
70.degree. C. for 2 h, the reaction solution was treated with about
300 ml of EA. The solution was washed with water and saturated
sodium chloride solution, and the organic phase was dried over
sodium sulfate and concentrated to dryness. The residual slightly
yellow oil was purified by chromatography on silica gel using EA.
Concentration of the product-containing fractions and drying in a
high vacuum yielded 7.25 g of the title compound as a pale yellow
solid.
[0194] M.p.: 134-136.degree. C.
[0195] R.sub.f (SiO.sub.2, EA)=0.35
[0196] MS (DCl): m/z=426 [M+H].sup.+
[0197] d)
5-(2-Aminoethyl)-2-(2-methoxyethoxy)benzenesulfonamide
[0198] A solution of 7.24 g (17.0 mmol) of the compound of example
2c) in 100 ml of methanol and 100 ml of half-concentrated
hydrochloric acid was heated to reflux for 8 h. About 40 ml of
ethanol were then added to the reaction solution and the deposited
precipitate was filtered off with suction. Washing of the
precipitate with cold ethanol and drying in a high vacuum yielded
4.0 g of the hydrochloride salt of the title compound as a white
solid.
[0199] M.p.: 230-233.degree. C.
[0200] MS (DCl): m/z=275 [M+H].sup.+
[0201] e)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-methoxyethoxy)benzenesu-
lfonamide
[0202] According to the process described in example 1d), starting
from 250 mg (0.80 mmol) of the compound of example 2d) and 167 mg
(0.97 mmol) of 3-quinolinecarboxylic acid, 133 mg of the title
compound were obtained as a white solid.
[0203] M.p.: 170.degree. C.
[0204] R.sub.f (SiO.sub.2, EA)=0.19
[0205] MS (ESI): m/z=430 [M+H].sup.+
[0206] f)
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-methoxyethoxy)phenyl-
sulfonyl]-3-methyl-thiourea
[0207] According to the process described in example 1e), starting
from 88 mg (0.20 mmol) of the compound of example 2e) and 224 .mu.l
(0.22 mmol) of a 1M solution of methyl isothiocyanate in absolute
DMF, 61 mg of the title compound were obtained as a pale yellow
amorphous solid after drying in a high vacuum.
[0208] R.sub.f (SiO.sub.2, EA)=0.33
[0209] MS (ESI): m/z=503 [M+H].sup.+
EXAMPLE 3
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-methoxyethoxy)phenylsulfonyl]--
3-methyl-urea
[0210] 30
[0211] 50 mg (0.10 mmol) of the compound of example 2f) were
dissolved in 1 ml of 1N sodium hydroxide solution. 450 .mu.l of a
35% strength aqueous hydrogen peroxide solution were added and the
resulting solution was heated on the water bath for 30 min. The pH
of the solution was then adjusted to 2 by addition of 2N
hydrochloric acid. The deposited precipitate was filtered off with
suction, washed with a little water and dried in a high vacuum. 20
mg of the title compound resulted as a pale yellow amorphous
solid.
[0212] R.sub.f (SiO.sub.2, EA)=0.08
[0213] MS (ESI): m/z=487 [M+H].sup.+
EXAMPLE 4
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-(2,2,2trifluoroethoxy)ethoxy)p-
henyl-sulfonyl]-3-methyl-thiourea
[0214] 31
[0215] a) 2-(2,2,2-Trifluoroethoxy)ethanol
[0216] A mixture of 36 ml (0.50 mol) of 2,2,2-trifluoroethanol, 66
g (0.75 mol) of ethylene carbonate and 70 ml (0.50 mol) of
triethylamine was heated to reflux for 16 h. Distillation of the
reaction mixture through a Vigreux column at normal pressure
yielded the title compound as a colorless liquid.
[0217] Boiling point: 132.degree. C.
[0218] MS (ESI): m/z=145 [M+H].sup.+
[0219] b)
N-Dimethylaminomethylene-2-(2-(2,2,2-trifluoroethoxy)ethoxy)-5-(-
2-(2,2,2-trifluoroacetamido)ethyl)benzenesulfonamide
[0220] 16.5 ml (55.5 mmol) of methanesulfonyl chloride were slowly
added dropwise to a solution of 8.0 g (55.5 mmol) of the compound
of example 4a) and 7.8 ml (55.5 mmol) of triethylamine in 50 ml of
absolute THF cooled to 0.degree. C. After stirring at RT for 15
min, the deposited triethylammonium chloride was filtered off with
suction and the filtrate was concentrated to dryness in vacuo. 6.7
g (30 mmol) of the 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate
obtained were added to 5.7 g (15.5 mmol) of the compound of example
2b) and 10 g of potassium carbonate in 150 ml of absolute DMF and
the resulting mixture was stirred at 110.degree. C. for 3 h. The
reaction solution was then poured onto 1 l of ice water. The
solution was extracted repeatedly with EA and the combined EA
extracts were washed with water, dried over sodium sulfate and
concentrated. Drying in a high vacuum yielded 6.8 g of the title
compound.
[0221] R.sub.f (SiO.sub.2, EA)=0.32
[0222] MS (ESI): m/z=494 [M+H].sup.+
[0223] c)
5-(2-Aminoethyl)-2-(2-(2,2,2-trifluoroethoxy)ethoxy)benzenesulfo-
namide
[0224] According to the process described in example 2d), starting
from 2.5 g (5.1 mmol) of the compound of example 4b), 1.3 g of the
title compound were obtained using hydrochloric acid.
[0225] R.sub.f (SiO.sub.2, EA)=0.06
[0226] MS (ESI): m/z=343 [M+H].sup.+
[0227] d)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-(2,2,2-trifluoroethoxy)-
ethoxy)benzenesulfonamide
[0228] According to the process described in example 1d), starting
from 1.0 g (2.64 mmol ) of the compound of example 4c) and 550 mg
(3.17 mmol) of 3-quinolinecarboxylic acid, 1.18 g of the title
compound were obtained as a white solid.
[0229] M.p.: 206-210.degree. C.
[0230] R.sub.f (SiO.sub.2, EA)=0.46
[0231] MS (ESI): m/z=498 [M+H].sup.+
[0232] e)
1-r5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-(2,2,2-trifluoroetho-
xy)ethoxy)phenyl-sulfonyl]-3-methyl-thiourea
[0233] According to the process described in example 1e), starting
from 120 mg (0.24 mmol) of the compound of example 4d) and 295
.mu.l (0.26 mmol) of a 1 M solution of methyl isothiocyanate in
absolute DMF, 85 mg of the title compound were obtained as a white
solid after drying in a high vacuum.
[0234] M.p.: 115-120.degree. C.
[0235] R.sub.f (SiO.sub.2, EA)=0.52
[0236] MS (ESI): m/z=571 [M+H].sup.+
EXAMPLE 5
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-(2,2,2trifluoroethoxy)ethoxy)p-
henyl-sulfonyl]-3-methyl-thiourea sodium salt
[0237] 32
[0238] 11 mg (0.28 mmol) of sodium hydroxide were dissolved in 5 ml
of absolute ethanol. 150 mg (0.26 mmol) of the compound of example
4e) were then added and the resulting solution was stirred at RT
for 5 h. The precipitate crystallizing from the solution was
filtered off with suction and dried in a high vacuum. 135 mg of the
title compound resulted as a white solid.
[0239] M.p.: 125.degree. C.
[0240] MS (FAB): m/z=571 [M--Na+H].sup.+, 593 [M+H].sup.+
EXAMPLE 6
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-(2,2,2trifluoroethoxy)ethoxy)p-
henyl-sulfonyl]-3-methyl-urea
[0241] 33
[0242] According to the process described in example 3), starting
from 40 mg (0.07 mmol) of the compound of example 4e), 24 mg of the
title compound were obtained as a pale yellow solid using hydrogen
peroxide.
[0243] M.p.: 128.degree. C.
[0244] R.sub.f (SiO.sub.2, EA)=0.47
[0245] MS (ESI): m/z=555 [M+H].sup.+
EXAMPLE 7
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-ethoxyphenylsulfonyl]-3-methyl-th-
iourea
[0246] 34
[0247] a)
N-Dimethylaminomethylene-2-ethoxy-5-(2-(2,2,2-trifluoroacetamido-
)ethyl)-benzenesulfonamide
[0248] A mixture of 2.0 g (5.44 mmol) of the compound of example
2b) and 1.88 g (13.61 mmol) of potassium carbonate in 10 ml of
absolute DMF was treated with 1.42 ml (19.05 mmol) of ethyl bromide
and stirred at 70.degree. C. for 2 h. The reaction solution was
then treated with about 10 ml of EA. The solution was washed with
water and saturated sodium chloride solution, and the organic phase
was dried over sodium sulfate and concentrated to dryness. The
resulting residue was triturated with a little EA and the
precipitate which remained was filtered off with suction. Drying in
a high vacuum yielded 915 mg of the title compound as a white
solid.
[0249] M.p.: 148-150.degree. C.
[0250] R.sub.f (SiO.sub.2, EA)=0.57
[0251] MS (FAB): m/z=396 [M+H].sup.+
[0252] b) 5-(2-Aminoethyl)-2-ethoxybenzenesulfonamide
[0253] According to the process described in example 1c), starting
from 910 mg (2.31 mmol) of the compound of example 7a), 490 mg of
the title compound were obtained as a white solid using
hydrochloric acid.
[0254] M.p.: 241-243.degree. C.
[0255] R.sub.f (SiO.sub.2, EA)=0.03
[0256] MS (ESI): m/z=281 [M+H].sup.+
[0257] c)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-ethoxybenzenesulfonamide
[0258] According to the process described in example 1d), starting
from 485 mg (1.73 mmol) of the compound of example 7b), 500 mg of
the title compound were obtained as an amorphous white solid.
[0259] M.p.: 222-231.degree. C.
[0260] R.sub.f (SiO.sub.2, EA)=0.45
[0261] MS (ESI): m/z=400 [M+H].sup.+
[0262] d)
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-ethoxyphenylsulfonyl]-3-
-methyl-thiourea
[0263] According to the process described in example 1e), starting
from 495 mg (1.24 mmol) of the compound of example 7c), 222 mg of
the title compound were obtained as a white solid using methyl
isothiocyanate.
[0264] M.p.: 189-193.degree. C.
[0265] R.sub.f (SiO.sub.2, EA)=0.42
[0266] MS (ESI): m/z=473 [M+H].sup.+
EXAMPLE 8
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-propyloxyphenylsulfonyl]-3-methyl-
-thiourea
[0267] 35
[0268] a)
N-Dimethylaminomethylene-2-propyloxy-5-(2-(2,2,2-trifluoroacetam-
ido)ethyl)-benzenesulfonamide
[0269] According to the process described in example 7a), starting
from 1.3 g (3.54 mmol) of the compound of example 2b), with
n-propyl bromide, 771 mg of the title compound were obtained as a
white solid after chromatographic purification on silica gel using
EA/n-heptane (8:1).
[0270] M.p.: 142.degree. C.
[0271] R.sub.f (SiO.sub.2, EA)=0.58
[0272] MS (ESI): m/z=410 [M+H].sup.+
[0273] b) 5-(2-Aminoethyl)-2-propyloxybenzenesulfonamide
[0274] According to the process described in example 1c), starting
from 768 mg (1.87 mmol) of the compound of example 8a), 418 mg of
the title compound were obtained as a white solid using
hydrochloric acid.
[0275] M.p.: 224-230.degree. C.
[0276] R.sub.f (SiO.sub.2, EA)=0.03
[0277] MS (DCl): m/z=295 [M+H].sup.+
[0278] c)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-propyloxybenzenesulfonamid-
e
[0279] According to the process described in example 1d), starting
from 414 mg (1.40 mmol) of the compound of example 8b), 302 mg of
the title compound were obtained as an amorphous white solid using
3-quinolinecarboxylic acid.
[0280] R.sub.f (SiO.sub.2, EA)=0.24
[0281] MS (ESI): m/z=414 [M+H].sup.+
[0282] d)
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-propyloxyphenylsulfonyl-
-3-methyl-thiourea
[0283] According to the process described in example 1e), starting
from 296 mg (0.72 mmol) of the compound of example 8c), 321 mg of
the title compound were obtained as a white solid using methyl
isothiocyanate.
[0284] M.p.: 108-110.degree. C.
[0285] R.sub.f (SiO.sub.2, EA)=0.47
[0286] MS (ESI): m/z=487 [M+H].sup.+
EXAMPLE 9
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-propyloxyphenylsulfonyl]-3-methyl-
-urea
[0287] 36
[0288] According to the process described in example 3), starting
from 70 mg (0.14 mmol) of the compound of example 8d), 37 mg of the
title compound were obtained as a pale yellow solid using hydrogen
peroxide.
[0289] M.p.: 120.degree. C.
[0290] R.sub.f (SiO.sub.2, EA)=0.38
[0291] MS (FAB): m/z=471 [M+H].sup.+
EXAMPLE 10
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-ethoxyethoxy)phenylsulfonyl]-3-
-methyl-thiourea
[0292] 37
[0293] a)
N-Dimethylaminomethylene-(2-(2-ethoxyethoxy)-5-(2-(2,2,2-trifluo-
roacetamido)-ethyl)benzenesulfonamide
[0294] A mixture of 2.0 g (5.44 mmol) of the compound of example
2b) and 1.88 g (6.80 mmol) of potassium carbonate in 10 ml of
absolute DMF was treated with 2.14 ml (13.61 mmol) of 2-bromoethyl
ethyl ether and stirred at 70.degree. C. for 1.5 h. The reaction
mixture was then treated with about 10 ml of EA. The mixture was
washed with water and saturated sodium chloride solution, and the
organic phase was dried over sodium sulfate and concentrated to
dryness. The residual colorless oil was purified by chromatography
on silica gel using EA/n-heptane (8:1). Concentration of the
product-containing fractions and drying in a high vacuum yielded
1.35 g of the title compound as a pale yellow solid.
[0295] M.p.: 88-91.degree. C.
[0296] R.sub.f (SiO.sub.2, EA)=0.40
[0297] MS (ESI): m/z=440 [M+H].sup.+
[0298] b) 5-(2-Aminoethyl)-2-(2-ethoxyethoxy)benzenesulfonamide
[0299] According to the process described in example 1c), starting
from 1.33 g (3.03 mmol) of the compound of example 10a), 700 mg of
the title compound were obtained as a white solid using
hydrochloric acid.
[0300] M.p.: 203-205.degree. C.
[0301] R.sub.f (SiO.sub.2, EA)=0.04
[0302] MS (ESI): m/z=289 [M+H].sup.+
[0303] c)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-ethoxyethoxy)benzenesul-
fonamide
[0304] According to the process described in example 1d), starting
from 695 mg (2.15 mmol) of the compound of example 10b), 754 mg of
the title compound were obtained as a white solid using
3-quinolinecarboxylic acid.
[0305] M.p.: 220-226.degree. C.
[0306] R.sub.f (SiO.sub.2, EA)=0.33
[0307] MS (ESI): m/z=444 [M+H].sup.+
[0308] d)
1-5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-ethoxyethoxy)phenylsu-
lfonyl]-3-methyl-thiourea
[0309] According to the process described in example 1e), starting
from 750 mg (1.69 mmol) of the compound of example 10c), 219 mg of
the title compound were obtained as a pale yellow solid using
methyl isothiocyanate.
[0310] M.p.: 50-52.degree. C.
[0311] R.sub.f (SiO.sub.2, EA)=0.47
[0312] MS (ESI): m/z=517 [M+H].sup.+
EXAMPLE 11
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2(2-phenoxyethoxy)phenylsulfonyl]-3-
-methyl-thiourea
[0313] 38
[0314] a)
N-Dimethylaminomethylene-(2-(2-phenoxyethoxy)-5-(2-(2,2,2-triflu-
oroacetamido)-ethyl)benzenesulfonamide
[0315] According to the process described in example 2c), starting
from 1.0 g (2.72 mmol) of the compound of example 2b) and 1.91 g
(9.53 mmol) of 2-phenoxyethyl bromide, 886 mg of the title compound
were obtained as a white solid.
[0316] M.p.: 89-91.degree. C.
[0317] R.sub.f (SiO.sub.2, EA)=0.57
[0318] MS (ESI): m/z=488 [M+H].sup.+
[0319] b)
5-(2-Aminoethyl)-2-(2-phenoxyethoxy)benzenesulfonamide
[0320] According to the process described in example 1c), starting
from 880 mg (1.81 mmol) of the compound of example 11a), 656 mg of
the title compound were obtained as a white solid using
hydrochloric acid.
[0321] M.p.: 215.degree. C.
[0322] R.sub.f (SiO.sub.2, EA)=0.02
[0323] MS (DCl): m/z=337 [M+H].sup.+
[0324] c)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-phenoxyethoxy)benzenesu-
lfonamide
[0325] According to the process described in example 1d), starting
from 252 mg (0.68 mmol) of the compound of example 11b), 222 mg of
the title compound were obtained as a white solid using
3-quinolinecarboxylic acid.
[0326] M.p.: 205-209.degree. C.
[0327] R.sub.f (SiO.sub.2, EA)=0.62
[0328] MS (ESI): m/z=492 [M+H].sup.+
[0329] d)
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-phenoxyethoxy)phenyl-
sulfonyl]-3-methyl-thiourea
[0330] According to the process described in example 1e), starting
from 108 mg (0.22 mmol) of the compound of example 11c), 121 mg of
the title compound were obtained as a slightly yellow solid using
methyl isothiocyanate.
[0331] M.p.: 110.degree. C.
[0332] R.sub.f (SiO.sub.2, EA)=0.48
[0333] MS (ESI): m/z=565 [M+H].sup.+
EXAMPLE 12
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-phenylethoxy)phenylsulfonyl]-3-
-methyl-thiourea
[0334] 39
[0335] a)
N-Dimethylaminomethylene-2-(2-phenylethoxy)-5-(2-(2,2,2-trifluor-
oacetamido)-ethyl)benzenesulfonamide
[0336] According to the process described in example 9a), starting
from 1.5 g (4.01 mmol) of the compound of example 2b), 1.21 g of
the title compound were obtained as a white solid using
2-phenylethyl bromide.
[0337] M.p.: 48.degree. C.
[0338] R.sub.f (SiO.sub.2, EA)=0.67
[0339] MS (ESI): m/z=472 [M+H].sup.+
[0340] b) 5-(2-Aminoethyl)-2-(2-phenylethoxy)benzenesulfonamide
[0341] According to the process described in example 1c), starting
from 1.2 g (2.54 mmol) of the compound of example 12a), 880 mg of
the title compound were obtained as a white solid using
hydrochloric acid.
[0342] M.p.: 207-212.degree. C.
[0343] R.sub.f (SiO.sub.2, EA)=0.73
[0344] MS (ESI): m/z=321 [M+H].sup.+
[0345] c)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-phenylethoxy)benzenesul-
fonamide
[0346] According to the process described in example 1d), starting
from 350 mg (0.98 mmol) of the compound of example 12b), 256 mg of
the title compound were obtained as a white solid using
3-quinolinecarboxylic acid.
[0347] M.p.: 232-236.degree. C.
[0348] R.sub.f (SiO.sub.2, EA)=0.52
[0349] MS (ESI): m/z=476 [M+H].sup.+
[0350] d)
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-phenylethoxy)phenyls-
ulfonyl]-3-methyl-thiourea
[0351] According to the process described in example 1e), starting
from 125 mg (0.26 mmol) of the compound of example 12c), 140 mg of
the title compound were obtained as a white solid using methyl
isothiocyanate.
[0352] M.p.: 124.degree. C.
[0353] R.sub.f (SiO.sub.2, EA)=0.48
[0354] MS (FAB): m/z=549 [M+H].sup.+
EXAMPLE 13
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2,2,2-trifluoroethoxy)phenylsulf-
onyl]-3-methyl-thiourea
[0355] 40
[0356] a)
N-Dimethylaminomethylene-2-(2,2,2-trifluoroethoxy)-5-(2-(2,2,2-t-
rifluoroacetamido)ethyl)benzenesulfonamide
[0357] A solution of 1.44 ml (20.0 mmol) of 2,2,2-trifluoroethanol,
2.77 ml (20.0 mmol) of triethylamine and 1.6 ml (20.5 mmol) of
methanesulfonyl chloride in 20 ml of absolute THF was stirred under
an argon atmosphere for 15 min. The precipitated triethylammonium
chloride was filtered off and the filtrate was evaporated. 2.7 g of
2,2,2-trifluoroethyl methanesulfonate remained as a colorless
liquid. 2.68 g (15.05 mmol) of this compound were dissolved in 80
ml of absolute DMF under an argon atmosphere, and 4.57 g (33.10
mmol) of potassium carbonate and 2.21 g (6.02 mmol) of the compound
of example 2b) were added. The resulting reaction mixture was
stirred at 110.degree. C. for 3 h and then poured onto 500 ml of
ice. The mixture was extracted repeatedly with EA, and the combined
EA phases were dried over sodium sulfate and concentrated.
Chromatographic purification of the residue on silica gel using EA
yielded 1.20 g of the title compound as a white solid.
[0358] M.p.: 130.degree. C.
[0359] R.sub.f (SiO.sub.2, EA)=0.73
[0360] MS (ESI): m/z=450 [M+H].sup.+
[0361] b)
5-(2-Aminoethyl)-2-(2,2,2-trifluoroethoxy)benzenesulfonamide
[0362] According to the process described in example 1c), starting
from 1.14 g (2.53 mmol) of the compound of example 13a), 345 mg of
the title compound were obtained as a white solid using
hydrochloric acid.
[0363] M.p.: 241.degree. C.
[0364] R.sub.f (SiO.sub.2, EA)=0.02
[0365] MS (ESI): m/z=335 [M+H].sup.+
[0366] c)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2,2,2-trifluoroethoxy)ben-
zenesulfonamide
[0367] According to the process described in example 1d), starting
from 340 mg (1.02 mmol) of the compound of example 13b), 66 mg of
the title compound were obtained as a white solid using
3-quinolinecarboxylic acid.
[0368] M.p.: 196-202.degree. C.
[0369] R.sub.f (SiO.sub.2, EA)=0.40
[0370] MS (ESI): m/z=453 [M+H].sup.+
[0371] d)
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2,2,2-trifluoroethoxy)-
phenylsulfonyl]-3-methyl-thiourea
[0372] According to the process described in example 1e), starting
from 55 mg (0.12 mmol) of the compound of example 13c), 52 mg of
the title compound were obtained as a pale yellow solid using
methyl isothiocyanate.
[0373] M.p.: 75.degree. C.
[0374] R.sub.f (SiO.sub.2, EA)=0.28
[0375] MS (ESI): m/z=527 [M+H].sup.+
EXAMPLE 14
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-furyl)phenylsulfonyl]-3-methyl-
-thiourea
[0376] 41
[0377] a) 2,2,2-Trifluoro-N-(2-(4-nitrophenyl)ethyl)acetamide
[0378] According to the process described in example 1a), starting
from 29.8 g (0.15 mol) of 2-(4-nitrophenyl)ethylamine
hydrochloride, 34.7 g of the title compound were obtained as a
beige solid using trifluoroacetic anhydride.
[0379] M.p.: 96-97.degree. C.
[0380] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.52
[0381] MS (ESI): m/z=263 [M+H].sup.+
[0382] b) 2,2,2-Trifluoro-N-(2-(4-aminophenyl)ethyl)acetamide
[0383] A solution of 34.6 g (0.13 mol) of the compound of example
14a) and 197 g (0.87 mol) of SnCl.sub.2.times.2 H.sub.2O in 1 l of
EA was stirred at 80.degree. C. for 3.5 h. The reaction solution
was then treated with 2 l of 10% strength sodium hydrogencarbonate
solution, the precipitate was filtered off and the organic phase
was separated. The organic phase was dried over sodium sulfate and
concentrated to dryness in vacuo. 26.9 g of the title compound
resulted as a pale brown solid.
[0384] M.p.: 81-85.degree. C.
[0385] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.35
[0386] MS (ESI): m/z=233 [M+H].sup.+
[0387] c) 2,2,2-Trifluoro-N-(2-(4-iodophenyl)ethyl)acetamide
[0388] A solution of 8.3 g (0.12 mol) of sodium nitrite in 28 ml of
water was added dropwise to a suspension of 26.8 g (0.11 mol) of
the compound of example 14b) in 125 ml of dilute hydrochloric acid
cooled to 0.degree. C. After stirring at this temperature for 15
min, a solution of 19.9 g (0.12 mol) of potassium iodide in 28 ml
of water was added dropwise and the resulting reaction solution was
stirred at RT for 3 h. The solution was extracted with DCM, and the
organic phase was separated off, washed with 10% strength sodium
hydrogensulfite solution and water and dried over sodium sulfate.
After concentration and chromatographic purification of the residue
on silica gel using DCM/EA (80:1), 17.1 g of the title compound
were obtained as a pale yellow solid.
[0389] M.p.: 136-138.degree. C.
[0390] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.67
[0391] MS (DCl): m/z=344 [M+H].sup.+
[0392] d)
2-lodo-5-(2-(2,2,2-trifluoroacetamido)ethyl)benzenesulfonamide
[0393] 10 g (29.1 mmol) of the compound of example 14c) were added
in portions to 95 ml of chlorosulfonic acid cooled to 0.degree. C.
After stirring at RT for 3.5 h, the reaction solution was added
dropwise to 400 ml of ice and the deposited precipitate was
filtered off with suction. This precipitate was dissolved in 200 ml
of acetone, and 56 ml of concentrated ammonia solution were added
dropwise to this solution with ice-cooling. After stirring at RT
for 45 min, the deposited precipitate was filtered off with suction
and the acetone was evaporated in a rotary evaporator. The solution
that remained was extracted with EA, and the EA phase was separated
off, washed with saturated sodium chloride solution and dried over
sodium sulfate. After concentration and chromatographic
purification of the residue on silica gel using EA/heptane (1:2),
4.5 g of the title compound were obtained.
[0394] M.p.: from 115.degree. C. (softening)
[0395] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.32
[0396] MS (ESI): m/z=423 [M+H].sup.+
[0397] e)
N-Dimethylaminomethylene-2-iodo-5-(2-(2,2,2-trifluoroacetamido)e-
thyl)benzene-sulfonamide
[0398] A solution of 2.9 g (6.87 mmol) of the compound of example
14d) and 1.26 ml (8.26 mmol) of N,N-dimethylformamide dimethyl
acetal in 16 ml of absolute DMF was stirred at RT for 1 h. The
mixture was concentrated to dryness in vacuo and the residue was
dissolved in 5 ml of DMF. 70 ml of a 5% strength sodium
hydrogensulfate solution was added dropwise to this solution at
0.degree. C., and the deposited precipitate was filtered off with
suction and washed with water. Drying in a high vacuum yielded 3.2
g of the title compound as a slightly yellow solid.
[0399] M.p.: 155-156.degree. C.
[0400] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.10
[0401] MS (ESI): m/z=478 [M+H].sup.+
[0402] f)
N-Dimethylaminomethylene-2-(2-furyl)-5-(2-(2,2,2-trifluoroacetam-
ido)ethyl)-benzenesulfonamide
[0403] 26.6 mg (0.03 mmol) of bis(triphenylphosphine)palladium(II)
chloride and 2.9 ml (9.28 mmol) of 2-(tri-n-butylstannyl)furan were
added under an argon atmosphere to a solution of 3.1 g (6.70 mmol)
of the compound of example 14e) in 30 ml of DMF. The resulting
reaction solution was heated to reflux for 8 h. The solution was
then diluted with EA, and washed with water and dried over sodium
sulfate. Chromatographic purification of the residue which remained
after stripping off the solvent, on silica gel using EA/n-heptane
(1:1) afforded 2.6 g of the title compound as a pale yellow
solid.
[0404] M.p.: 150.degree. C.
[0405] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.06
[0406] MS (ESI): m/z=418 [M+H].sup.+
[0407] g) 5-(2-Aminoethyl)-2-(2-furyl)benzenesulfonamide
[0408] A solution of 2.6 g (6.23 mmol) of the compound of example
14f) and 9 ml of 2N sodium hydroxide solution in 46 ml of ethanol
was stirred at 80.degree. C. for 2 h. After cooling to RT, the pH
of the solution was adjusted to 7 by addition of concentrated
acetic acid, and the solution was concentrated to dryness. Drying
of the residue in a high vacuum yielded 1.6 g of the title compound
as a colorless oil.
[0409] R.sub.f (SiO.sub.2, EA)=0.10
[0410] MS (ESI): m/z=267 [M+H].sup.+
[0411] h)
5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-furyl)benzenesulfonamid-
e
[0412] According to the process described in example 1d), starting
from 1.5 g (1.68 mmol) of the compound of example 14g), 536 mg of
the title compound were obtained as a white solid using
3-quinolinecarboxylic acid.
[0413] M.p.: 196.degree. C.
[0414] R.sub.f (SiO.sub.2, EA/n-heptane 4:1)=0.12
[0415] MS (ESI): m/z=422 [M+H].sup.+
[0416] i)
1-[5-(2-(3-Quinolinecarboxamido)ethyl)-2-(2-furyl)phenylsulfonyl-
]-3-methyl-thiourea
[0417] According to the process described in example 1e), starting
from 260 mg (0.62 mmol) of the compound of example 14 h), 210 mg of
the title compound were obtained as an amorphous solid using methyl
isothiocyanate.
[0418] R.sub.f (SiO.sub.2, EA/n-heptane 4:1)=0.28
[0419] MS (ESI): m/z=495 [M+H].sup.+
EXAMPLE 15
1-[5-(2-(3-Methylbut-2-eneamido)ethyl)-2-methoxyphenylsulfonyl]-3-methyl-t-
hiourea
[0420] 42
[0421] a)
5-(2-(3-Methylbut-2-eneamido)ethyl)-2-methoxybenzenesulfonamide
[0422] According to the process described in example 1d), starting
from 465 mg (2.02 mmol) of the compound of example 1c), 199 mg of
the title compound were obtained as a white solid using
3,3-dimethylacrylic acid.
[0423] M.p.: 156-160.degree. C.
[0424] R.sub.f (SiO.sub.2, EA/n-heptane 4:1)=0.21
[0425] MS (ESI): m/z=313 [M+H].sup.+
[0426] b)
1-[5-(2-(3-Methylbut-2-eneamido)ethyl)-2-methoxyphenylsulfonyl]--
3-methyl-thiourea
[0427] According to the process described in example 1e), starting
from 90 mg (0.30 mmol) of the compound of example 15a), 66 mg of
the title compound were obtained as a white solid using methyl
isothiocyanate.
[0428] M.p.: 153-154.degree. C.
[0429] R.sub.f (SiO.sub.2, EA/n-heptane 8:1)=0.42
[0430] MS (ESI): m/z=386 [M+H].sup.+
EXAMPLE 16
1-[5-(2-(3-Methylbut-2-eneamido)ethyl)-2-methoxyphenylsulfonyl]-3-methyl-u-
rea
[0431] 43
[0432] According to the process described in example 3), starting
from 45 mg (0.12 mmol) of the compound of example 15b), 17 mg of
the title compound were obtained as a white solid using hydrogen
peroxide.
[0433] M.p.: 199-203.degree. C.
[0434] R.sub.f (SiO.sub.2, EA/n-heptane 8:1)=0.09
[0435] MS (ESI): m/z=370 [M+H].sup.+
EXAMPLE 17
1-[5-(2-(3-Methylbut-2-eneamido)ethyl)-2-(2-methoxyethoxy)phenylsulfonyl]--
3-methyl-thiourea
[0436] 44
[0437] a)
5-(2-(3-Methylbut-2-eneamido)ethyl)-2-(2-methoxyethoxy)benzenesu-
lfonamide
[0438] According to the process described in example 1d), starting
from 500 mg (1.61 mmol) of the compound of example 2c), 190 mg of
the title compound were obtained as a white solid using
3,3-dimethylacrylic acid.
[0439] M.p.: 120-127.degree. C.
[0440] R.sub.f (SiO.sub.2, EA/n-heptane 4:1)=0.15
[0441] MS (ESI): m/z=357 [M+H].sup.+
[0442] b)
1-[5-(2-(3-Methylbut-2-eneamido)ethyl)-2-(2-methoxyethoxy)phenyl-
sulfonyl]-3-methyl-thiourea
[0443] According to the process described in example 1e), starting
from 185 mg (0.53 mmol) of the compound of example 17a), 68 mg of
the title compound were obtained as a white amorphous solid using
methyl isothiocyanate.
[0444] R.sub.f (SiO.sub.2, EA/n-heptane 4:1)=0.37
[0445] MS (ESI): m/z=430 [M+H].sup.+
EXAMPLE 18
1-[5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-methoxyphenylsulfonyl]-3-met-
hyl thiourea
[0446] 45
[0447] a)
5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-methoxybenzenesulfona-
mide
[0448] According to the process described in example 1d), starting
from 465 mg (2.02 mmol) of the compound of example 1c), 598 mg of
the title compound were obtained as a white solid using
1-cyclohex-1-enecarboxylic acid.
[0449] M.p.: 155-157.degree. C.
[0450] R.sub.f (SiO.sub.2, EA/n-heptane 4:1)=0.21
[0451] MS (ESI): m/z=339 [M+H].sup.+
[0452] b)
1-[5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-methoxyphenylsulfo-
nyl]-3-methyl-thiourea
[0453] According to the process described in example 1e), starting
from 197 mg (0.58 mmol) of the compound of example 18a), 204 mg of
the title compound were obtained as a white solid using methyl
isothiocyanate.
[0454] M.p.: 179-182.degree. C.
[0455] R.sub.f (SiO.sub.2, EA/n-heptane 8:1)=0.42
[0456] MS (ESI): m/z=412 [M+H].sup.+
EXAMPLE 19
1-[5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-methoxyphenylsulfonyl]-3-met-
hyl-urea
[0457] 46
[0458] According to the process described in example 3), starting
from 70 mg (0.17 mmol) of the compound of example 18b), 57 mg of
the title compound were obtained as a white solid using hydrogen
peroxide.
[0459] M.p.: 175.degree. C.
[0460] R.sub.f (SiO.sub.2, EA/n-heptane 8:1)=0.15
[0461] MS (ESI): m/z=396 [M+H].sup.+
EXAMPLE 20
1-[5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-methoxyphenylsulfonyl]-3-iso-
propyl-thiourea
[0462] 47
[0463] According to the process described in example 1e), starting
from 197 mg (0.58 mmol) of the compound of example 18a), 213 mg of
the title compound were obtained as a white solid using isopropyl
isothiocyanate.
[0464] M.p.: 80-85.degree. C.
[0465] R.sub.f (SiO.sub.2, EA/n-heptane 8:1)=0.50
[0466] MS (ESI): m/z=440 [M+H].sup.+
EXAMPLE 21
1-[5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-methoxyphenylsulfonyl]-3-cyc-
lohexyl-thiourea
[0467] 48
[0468] According to the process described in example 1e), starting
from 197 mg (0.58 mmol) of the compound of example 18a), 272 mg of
the title compound were obtained as a white solid using cyclohexyl
isothiocyanate.
[0469] M.p.: 171-173.degree. C.
[0470] R.sub.f (SiO.sub.2, EA/n-heptane 8:1)=0.53
[0471] MS (ESI): m/z=480 [M+H].sup.+
EXAMPLE 22
1-[5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-(2-methoxyethoxy)phenylsulfo-
nyl]-3-methyl-thiourea
[0472] 49
[0473] a)
5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-(2-methoxyethoxy)benz-
enesulfonamide
[0474] According to the process described in example 1d), starting
from 500 mg (1.61 mmol) of the compound of example 2c), 280 mg of
the title compound were obtained as a pale yellow solid using
1-cyclohex-1-enecarboxylic acid.
[0475] M.p.: 165-172.degree. C.
[0476] R.sub.f (SiO.sub.2, EA/n-heptane 4:1) 0.11
[0477] MS (ESI): m/z=383 [M+H].sup.+
[0478] b)
1-[5-(2-(1-Cyclohex-1-enecarboxamido)ethyl)-2-(2-methoxyethoxy)p-
henylsulfonyl]-3-methyl-thiourea
[0479] According to the process described in example 1e), starting
from 135 mg (0.35 mmol) of the compound of example 22a), 106 mg of
the title compound were obtained as a beige solid using methyl
isothiocyanate.
[0480] M.p.: 150-155.degree. C.
[0481] R.sub.f (SiO.sub.2, EA/n-heptane 8:1)=0.22
[0482] MS (ESI): m/z=456 [M+H].sup.+
[0483] Pharmacological investigations
EXAMPLE 23
Action Potential Duration on the Papillary Muscle of the Guinea
Pig
[0484] ATP deficiency states observed during ischemia in the
cardiac muscle cell, lead to a shortening of the action potential
duration (ATP=adenosine triphosphate). They are regarded as one of
the causes of so-called reentry arrhythmias, which can cause sudden
cardiac death. The opening of ATP-sensitive potassium channels by
the lowering of the ATP level is regarded as the cause of this. For
the measurement of the action potential on the papillary muscle of
the guinea pig a standard microelectrode technique was
employed.
[0485] Guinea pigs of both sexes were killed by a blow to the head,
the hearts were removed, and the papillary muscles were separated
out and suspended in an organ bath. The organ bath was rinsed with
Ringer's solution (136 mmol/l of NaCl, 3.3 mmol/l of KCl, 2.5
mmol/l of CaCl.sub.2, 1.2 mmol/l of KH.sub.2PO.sub.4, 1.1 mmol/l of
MgSO.sub.4, 5.0 mmol/l of glucose, 10.0 mmol/l of
1-(2-hydroxyethyl)piperazine-4-(2-ethan- esulfonic acid) (HEPES),
pH adjusted to 7.4 with NaOH) and aerated with 100% oxygen at a
temperature of 37.degree. C. The muscle was stimulated with
square-wave pulses of 1 V and 1 ms duration and a frequency of 1 Hz
by means of an electrode. The action potential was derived and
recorded by means of a glass microelectrode inserted
intracellularly, which was filled with 3 mol/l of KCl solution. The
compound to be tested was added to the Ringer's solution in a
concentration of 2 .mu.mol/l. The action potential was amplified
using an amplifier from Hugo Sachs (March-Hugstetten, Germany) and
stored and analyzed by means of a computer. The duration of the
action potential was determined at a degree of repolarization of
90% (APD.sub.90). After an equilibration time of 30 min, the action
potential shortening was produced by rinsing the papillary muscle
with a hypoxic NaCl solution. The glucose was removed here, the
HEPES buffer replaced by PIPES buffer (piperazine-1,4-bis(2-eth-
anesulfonic acid)), the pH was adjusted to 6.5 and the aeration was
carried out using 100% nitrogen. After a time of 60 min, this led
to a marked shortening of the APD.sub.90. After this time, the test
compound was added and the relengthening of the action potential
recorded after a further 60 min. The compound-caused relengthening
of the APD.sub.90 was calculated as a percentage, in relation to
the shortening caused by hypoxia. The test compounds were added to
the bath solution as stock solution in propanediol.
[0486] The following relengthenings of the APD.sub.90 values were
observed.
2 Relengthening of the APD.sub.90 Compound Concentration shortened
by hypoxia Example 2 2 .mu.M 42% Example 4 2 .mu.M 69% Example 8 2
.mu.M 35% Example 17 2 .mu.M 34%
[0487] The observed values confirm the normalizing action of the
compounds according to the invention on a hypoxically shortened
action potential duration.
EXAMPLE 24
Chloroform-induced Ventricular Fibrillation in the Mouse (action in
the case of vagal dysfunction)
[0488] Hypoactivity of the vagal nervous system leads to
hyperactivity of the sympathetic nervous system. Damages to health
that result from an inequilibrium of the autonomic nervous system
when the dysfunction affects the heart include the weakening of the
myocardial contractile force and fatal cardiac arrhythmias such as
ventricular fibrillation. The action of the test compounds was
investigated in the model of chloroform-induced ventricular
fibrillation in the mouse (see J. W. Lawson, Antiarrhythmic
activity of some isoquinoline derivatives determined by a rapid
screening procedure in the mouse; J. Pharmacol. Exp. Ther. 160
(1968) 22).
[0489] The test compound was dissolved in a mixture of dimethyl
sulfoxide (DMSO) and 10 percent sodium hydrogencarbonate solution
and administered intraperitoneally (i.p.). The dose was 3 mg/kg. 30
min later, the mouse was anesthetized with chloroform in a beaker.
As soon as respiratory arrest had occurred under deep anesthesia
(toxic stage of anesthesia), the thorax of the animal was opened
using a pair of scissors and the heartbeat was visually inspected.
It can be determined here at a glance whether the heart is beating,
fibrillating, or has stopped. The respiratory arrest induced by
chloroform leads, via an absolute anoxia (oxygen deficiency) in
combination with a direct stimulating action of chloroform on the
sympathetic nervous system to a strong stimulation of the
sympathetic nervous system, which in turn, and in combination with
the energy deficiency caused by oxygen deficiency, leads in the
heart to the fatal arrhythmia, ventricular fibrillation. This toxic
chloroform anesthesia led to ventricular fibrillation in 100% of
the untreated mice (control). The percentage proportion of the mice
with ventricular fibrillation in the individual test groups
(consisting of n animals) is indicated as the fibrillation
ratio.
[0490] The following fibrillation ratios were observed.
3 Compound Fibrillation ratio (in %) Untreated control (n = 300)
100% Example 20 (n = 10) 70% Example 21 (n = 10) 70%
[0491] The reduction of the percentage proportion of mice having
ventricular fibrillation in comparison with the control (with a
100% fibrillation ratio) confirms that the compounds of the
invention significantly prevent the occurrence of ventricular
fibrillation.
EXAMPLE 25
Action on hSUR1/hKir6.2-transfected CHO Cells (hypoglycemic
action)
[0492] The mechanism of action of hypoglycemic sulfonylureas such
as, for example, glibenclamide has been roughly elucidated. The
target organ of these compounds is the D cell of the pancreas where
they block ATP-sensitive potassium channels and produce a release
of the hypoglycemic hormone insulin by influencing the electrical
potential of the cell membrane.
[0493] In molecular biology terms, pancreatic ATP-sensitive
potassium channels are composed of the sulfonylurea receptor SUR1
and the inwardly rectifying potassium channel Kir6.2 (Inagaki et
al., Science 270 (1995) 1166; Inagaki et al., Neuron 16 (1996)
1011). A hypoglycemic compound such as, for example, glibenclamide
brings about, by binding to the sulfonylurea receptor, a
depolarization of the cell membrane, which leads to an increased
influx of calcium ions, and as a consequence thereof, to a release
of insulin. The extent of this depolarization of the cell membrane,
which is caused by the compounds according to the invention, was
investigated on CHO cells that were transfected with the cloned
components of human pancreatic ATP-sensitive potassium channels,
hSUR1, and hKir6.2, and activated by pretreatment with diaxozide,
an opener of ATP-sensitive potassium channels. The potency of a
compound with respect to the membrane potential of these
transfected and activated CHO cells is a measure of the
hypoglycemic potential of this compound.
[0494] The CHO cells that showed a stable expression of human SUR1
and Kir6.2 were inoculated into 96-well microtiter plates on the
day before measurement. On the day of measurement, the microtiter
plates were washed three times with PBS (physiological buffer
solution). In the last washing step, 90 .mu.l remained in each
well. The cells were then loaded with the fluorescent dye
DIBAC.sub.4 (Molecular Probes, Portland, Oreg., USA) by addition of
90 .mu.l of a 10-micromolar solution of DIBAC.sub.4 in PBS and of
90 .mu.l of a 400 micromolar solution of diaxozide in PBS to each
well. After an incubation time of 30 min at 37.degree. C., the
microtiter plates were then transferred to a fluorescent microtiter
plate reader (FLIPR; Molecular Devices, Sunnyvale, Calif., USA).
The cells were stimulated by means of an argon laser (Innova 90;
Coherent, Santa Clara, Calif., USA) at a wavelength of 488 nm and
the fluorescence emission was measured by means of a CCD camera.
The measurement of the membrane potential began after 4 min by
addition of 20 .mu.l of a solution of the test compound or of the
control solution to each well, the resulting fluorescence emission
being measured every 20 seconds for a period of 20 min. The data
shown are mean values of at least 4 experiments.
[0495] The following results were obtained.
4 Compound Concentration Blockade hSUR1/hKir6.2 Glibenclamide
(hypoglycemic 0.01 .mu.M 92.7% comparison substance) Example 2 10
.mu.M 6.1% Example 3 10 .mu.M 0% Example 4 10 .mu.M 69.8% Example
11 10 .mu.M 67.5% Example 20 10 .mu.M 38.3%
[0496] The obtained results confirm that the compounds according to
the invention have no or an only very slight hypoglycemic
action.
* * * * *